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Advanced Drug Delivery Reviews 97 (2016) 41–55

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

The extracellular matrix in breast cancer☆


Jacob Insua-Rodríguez a,b, Thordur Oskarsson a,b,c,⁎
a
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
b
Cell Biology and Tumor Biology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
c
German Cancer Consortium (DKTK), Heidelberg, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The extracellular matrix (ECM) is increasingly recognized as an important regulator in breast cancer. ECM in
Received 22 September 2015 breast cancer development features numerous changes in composition and organization when compared to
Received in revised form 18 December 2015 the mammary gland under homeostasis. Matrix proteins that are induced in breast cancer include fibrillar colla-
Accepted 19 December 2015
gens, fibronectin, specific laminins and proteoglycans as well as matricellular proteins. Growing evidence sug-
Available online 30 December 2015
gests that many of these induced ECM proteins play a major functional role in breast cancer progression and
Keywords:
metastasis. A number of the induced ECM proteins have moreover been shown to be essential components of
Extracellular matrix metastatic niches, promoting stem/progenitor signaling pathways and metastatic growth. ECM remodeling en-
Breast cancer zymes are also markedly increased, leading to major changes in the matrix structure and biomechanical proper-
Metastasis ties. Importantly, several ECM components and ECM remodeling enzymes are specifically induced in breast
Niche cancer or during tissue regeneration while healthy tissues under homeostasis express exceedingly low levels.
Therapy This may indicate that ECM and ECM-associated functions may represent promising drug targets against breast
cancer, providing important specificity that could be utilized when developing therapies.
© 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2. ECM components in breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.1. Collagens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.2. Fibronectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.3. Laminins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4. Glycosaminoglycans and proteoglycans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4.1. Hyaluronan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4.2. Versican . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2.4.3. Decorin and lumican . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.4.4. Syndecans and glypicans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.5. Matricellular proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.5.1. Osteopontin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.5.2. Tenascin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
2.5.3. Periostin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
2.5.4. SPARC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
2.5.5. Thrombospondins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3. ECM remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.1. Matrix metalloproteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.2. Heparanase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.3. Cathepsins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.4. Urokinase plasminogen activator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.5. Lysyl oxidases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Extracellular Matrix (ECM) and ECM-like materials: Therapeutic Tools and Targets in Cancer Treatment”.
⁎ Corresponding author at: Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), German Cancer Research Center (DKFZ), Im Neuenheimer Feld
280, D-69120 Heidelberg, Germany. Tel.: +49 6221/42 3903.
E-mail address: t.oskarsson@dkfz.de (T. Oskarsson).

http://dx.doi.org/10.1016/j.addr.2015.12.017
0169-409X/© 2015 Elsevier B.V. All rights reserved.
42 J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55

4. Therapeutic opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

1. Introduction and biomechanical cues and are receiving increased attention as signif-
icant biological players in breast cancer progression and metastasis [5,
Breast cancer is the leading type of malignancy in women with 1.7 6]. The matrix is composed of numerous proteins that contribute to
million new cases diagnosed worldwide in 2012 [1]. While significant ECM structure and function such as collagens, fibronectin, laminins,
progress has been made in breast cancer diagnosis and early treatment, glycosaminoglycans and proteoglycans, matricellular proteins and
this malignancy still accounts for over half a million deaths yearly [1]. ECM remodeling enzymes. In breast cancer, significant changes occur
Most cancer-related deaths are associated with spread of malignant in ECM composition (Fig. 1). Interestingly, the ECM in breast cancer ex-
cells to distant sites of the body, leading to growth of new tumors, me- hibits high similarity with the matrix in tissues undergoing wound
tastases, in secondary organs [2]. Although early breast cancer can be healing or remodeling [5,7,8]. This includes the process of mammary
treated with good results, metastasis is exceedingly difficult to inhibit gland involution, which is the mammary gland reversal to its homeo-
and manage clinically. Thus, there is urgent need to better understand static state after pregnancy. Mammary gland involution is associated
the molecular mechanisms leading to metastatic growth to enable de- with extensive changes in the ECM, including strong upregulation of
velopment of new treatments or prevention strategies for advanced fibrillar collagens, fibronectin, matricellular proteins and a number of
breast cancer. ECM remodeling enzymes [9–11]. Moreover, ECM extracts from invo-
The importance of the tumor microenvironment in cancer progres- luting mammary glands promote aggressive behavior of cancer cells,
sion is widely recognized [3,4]. The microenvironment is composed of when co-implanted in animal models, leading to metastatic progression
a broad selection of distinct cell types, such as immune cells, fibroblasts, [12,13]. This phenomenon has been associated with the transient in-
endothelial cells and adipocytes, and an extracellular matrix (ECM). The crease in risk of breast cancer in women following pregnancy [11].
ECM is a highly dynamic and complex molecular network surrounding Evidence indicates that ECM composition continues to change dur-
cells within tissues. ECM components provide cells with biochemical ing cancer progression and may promote metastatic spread. Proteomic

Normal mammary gland Breast cancer

Basement Membrane: Interstitial ECM:


Disruption of basement membrane
• Laminins • Fibrillar collagens (I, III, V)
• Decreased collagen IV, laminin-111,
• Collagen IV • Fibronectin
• Increased ECM remodeling: MMP-2,
• Nidogens (entactins) • Decorin
-3, -9, -14; cathepsin-B, -K;
• Perlecan • Biglycan
urokinase plasminogen activator,
heparanase

Stiffer interstitial ECM


Tumorigenesis • Increased LOX activity
• Increased fibrillar collagens (I, III, V),
Primary site fibronectin, hyaluronan
Increased matricellular proteins
• Tenascin C
• Periostin
• Osteopontin
Vasculature • SPARC
• Thrombospondin-1
Proteoglycans
• Versican, syndecan-1, glypican-1

Autocrine TNC

Paracrine Luminal epithelial cell


Autocrine TNC TNC
Metastatic
Basal cell
colonization
Distant organ Stromal fibroblast
Collagen I
Stromal myofibroblast
Paracrine POSTN LOX
Breast cancer cell
Metastasis

Fig. 1. ECM changes in breast cancer progression and metastasis. The primary components of the ECM in normal mammary gland are significantly changed in breast cancer. A desmoplastic
reaction is associated with breast cancer development, due to the increased production of fibrous ECM by activated fibroblasts and cancer cells. The increased collagen deposition and
crosslinking by lysyl oxidase (LOX) enzymes, together with the increased production of fibronectin and other ECM components, stiffens the ECM, which in turn promotes tumor
aggressiveness. The basement membrane surrounding the mammary gland epithelium is broken down by ECM remodeling enzymes like MMPs, heparanase and others. Matricellular
proteins that promote cancer cell fitness such as tenascin C, periostin, osteopontin, SPARC and thrombospondin-1 are also upregulated. Breast cancer cells from the primary tumor,
that include cells with the ability to establish metastatic colonies, enter the blood circulation, disseminate and can reach distant sites. While the vast majority of disseminated cancer
cells are eliminated or undergo dormancy due to the adverse environment, few cancer cells are able to resist the selective pressure and establish a metastatic colony. These cells may
rely on signals from the ECM such as type I collagen (collagen I), crosslinked by LOX. Tenascin C (TNC) and periostin (POSTN), which are crucial ECM proteins of the metastatic niche,
promote stem/progenitor pathways and metastatic fitness in disseminated breast cancer cells.
J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55 43

analysis of the ECM in mammary tumors from xenograft mouse models However, when these cells are grown under high-density collagen con-
showed that tumors with high metastatic ability display distinct ECM ditions, they form disorganized and highly proliferative cell clusters that
composition when compared to less metastatic tumors [14]. Further- become invasive when treated with HGF [27]. Increased tissue tension
more, breast cancer patients stratified according to ECM composition strengthens the linkage between cytoskeleton and integrins which are
exhibit different clinical outcome [15]. Modulating functions of key important receptors mediating cell–matrix adhesions [28]. Integrins
ECM components by targeting the pro-tumorigenic signals or promot- consist of α/β heterodimers that typically bind to a variety of ECM com-
ing tumor suppressive signals mediated by the matrix, may represent ponents and mediate signaling. Matrix tension regulates mammary ep-
a promising strategy to tackle breast cancer progression. In this review, ithelial cell differentiation via a Rho-associated protein kinase (ROCK)-
we discuss the biological impact of the diverse ECM components in- dependent mechanism [29]. Furthermore, in mammary epithelial cells
volved in breast cancer progression and metastasis. Moreover, we ex- increased stiffness promotes activation of the mitogen-activated protein
amine the molecular mechanisms implicated in the dynamics and kinase (MAPK) pathway and induces proliferation [27,30]. Studies in
remodeling of cancer-associated ECM. Finally, we describe experimen- mouse models for breast cancer indicate that this mechanism may
tal evidence for how modulation of specific constituents of the ECM sig- also mediate a stiffness-induced aggressive phenotype in tumors [31].
naling axis may be a promising therapeutic option against breast cancer. Moreover, increased ECM stiffness has been shown to promote tran-
scriptional coactivator with PDZ-binding motif (TAZ) activity in breast
2. ECM components in breast cancer cancer cells, leading to an increase in tumor-initiating cells, also termed
cancer stem cells (CSCs) [32,33]. This suggests that increased ECM stiff-
2.1. Collagens ness may contribute to breast cancer progression by promoting self-
renewal ability of CSCs. In a mouse model for breast cancer metastasis,
A common feature of fibrosis and malignant breast cancer is the ex- collagen type I-induced cancer cell proliferation has been suggested to
cessive production of collagens. Collagens are major components of the mediate activation from dormancy [34]. For breast cancer patients, dor-
ECM, accounting for about 30% of the total protein mass in the body [16]. mancy can last for several years where the risk of recurrence still re-
There are 28 different types of collagens that are found in fibrillar and mains. In a genetic mouse model, increased ECM stiffness was
non-fibrillar forms. The most common collagen in mammals is the fibril- observed during tumor progression and associated with induction of
lar type I collagen, which is a principal component of interstitial matri- phosphoinositide 3-kinase (PI3K) signaling and invasive behavior in
ces. Type IV collagen is non-fibrillar and an essential constituent of the breast cancer cells [24]. Matrix density can promote formation of
basement membrane, a specialized type of ECM that is located at the invadopodia, which are actin-rich protrusions important for cell inva-
basal side of epithelial and endothelial sheets and is required for the sion [35]. Interestingly, stiff matrix induces a gene expression signature
maintenance of tissue polarity [16]. Significant changes in collagen com- in cancer cells that associates with poor clinical outcome in breast can-
position are observed in breast cancer where increased accumulation of cer patients [27]. Tissue stiffness not only predicts poor relapse-free sur-
fibrillar collagens I, III, and V occurs, and type IV collagen is decreased [5, vival, but is also linked to reduced response to breast cancer therapy and
7,16]. The noted reduction of type IV collagen in breast cancer is primar- short overall survival [27,36].
ily due to degradation of the basement membrane, which is also a com-
mon feature of the involuting mammary gland [5,7]. Certain collagens 2.2. Fibronectin
are present in gene signatures expressed in primary human breast can-
cer samples and are associated with increased risk of metastatic recur- Fibronectin (FN) is a fibril-forming glycoprotein that is, like collagen,
rence [17,18]. Increased expression of fibrillar collagens, such as type I strongly upregulated during fibrotic response or desmoplasia. Some
and type III collagens in breast cancer, may be linked to tumor invasion studies indicate that FN is required for collagen incorporation into the
and aggressive behavior [19]. In line with these observations, a fibrotic ECM [37]. In cancer, FN has been shown to be expressed by both
reaction associated with malignancies, termed desmoplasia, correlates cancer-associated fibroblasts (CAFs) and cancer cells themselves.
with poor prognosis in breast cancer patients [20]. Upregulation of FN in cancer cells can occur via distinct mechanisms.
The association between changes in collagen production and breast Mechanical compression can lead to increased migratory behavior
cancer progression may be functionally important and can be explained within tumors where cancer cells that lead the invasion express FN
by different means. Collagens can act as a scaffold, facilitating migration [38]. Interestingly, microRNA let7g was shown to regulate FN and its re-
of invading cancer cells or stromal cells [21]. In addition, increased col- pression in non-metastatic cancer cells led to FN upregulation and ac-
lagen deposition and modified fibril organization is associated with quisition of metastatic behavior [39]. In mouse models, FN expression
major changes in biomechanical properties of tissues. This may be af- has been reported to be induced in secondary organs by cytokines
fected by other ECM proteins, such as fibronectin, which forms fibrils secreted from the primary tumor, a process that can generate a stromal
within the matrix and has been suggested to promote the formation niche that promotes metastasis, a pre-metastatic niche [40]. Generally,
of collagen fibrils [22]. Moreover, collagen organization and stiffness is FN expression in breast cancer is associated with poor clinical outcome.
significantly affected by enzymatic modification such as crosslinking, Some studies indicate that cancer cell-derived FN, in particular, is linked
which will be discussed in further detail later in this review. Increased to poor metastasis free- and overall survival in breast cancer patients
tissue density is often observed in malignant breast cancer and growing [41,42]. Furthermore, FN expression has been detected in circulating
evidence suggests that high tissue tension may significantly influence tumor cells (CTCs) in breast cancer patients [43]. Evidence from patient
cancer progression [23,24]. Furthermore, high tissue density detected samples indicates that CTCs may show attributes of epithelial–mesen-
with radio-imaging within the apparently normal breast has been chymal transition (EMT) where cells lose polarity and cell–cell adhesion
linked to increased risk of breast cancer occurrence and studies using observed in epithelium and acquire a mesenchymal phenotype with
animal models suggest that this link has a causal significance [23,25]. high motility [44]. FN is an established mesenchymal marker and has
Recent evidence from mouse models indicates that changes in intersti- been shown to promote transforming growth factor beta (TGFβ)-in-
tial matrix and increased stiffness may be induced by obesity and can duced EMT [45]. Indeed, FN-positive CTCs express several EMT markers
promote mammary tumorigenesis [26]. [43].
Stromal stiffness has a significant effect on biochemical signaling and FN can have modulating effects on signaling pathways in cancer
cellular behavior of mammary cells and breast cancer cells. Non- cells. For example, FN was shown to induce the signal transducer and
transformed mammary epithelial cells form polarized acinar structures activator of transcription 3 (STAT3) signaling pathway and MAPK path-
when grown in low-density collagen matrix and generate an organized way in breast cancer cells, promoting invasion and metastasis in model
tubular network in response to hepatocyte growth factor (HGF) [27]. systems [39,46]. Moreover, FN can direct the cellular responses in
44 J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55

cancer cells to combined stimulation of insulin-like growth factor bind- thus confer mechanic support for tissues. Most GAGs are found
ing protein 3 (IGFBP-3) and epidermal growth factor (EGF). In the pres- covalently bound to core proteins, forming proteoglycans. Both pro-
ence of FN, IGFBP-3 and EGF treatment promotes growth, whereas in tein-bound and unbound GAGs have been shown to play a role in breast
the absence of FN these growth factors inhibit growth [47]. Together, cancer.
evidence indicates that FN may modulate cancer cell signaling in dis-
tinct manner and is an important promoter of breast cancer progression. 2.4.1. Hyaluronan
Hyaluronan (HA) is a GAG that is not bound to a protein core. HA
2.3. Laminins plays numerous biological roles in both physiological and pathophysio-
logical processes, depending on its polymer size and interactions with
Laminins form a group of large heterotrimeric glycoproteins and other secreted proteins and cell receptors. HA is essential for embryo-
represent the main non-collagenous proteins of basement membranes. genesis, morphogenesis, tissue repair and inflammation. Moreover, HA
12 different laminin forms are known that have cell- and tissue-specific is involved in the progression of cancer and is highly increased in breast
expression and are recognized by integrins and other receptors [48]. cancer in comparison to normal breast tissue [63]. Importantly, HA can
Several laminin isoforms play significant roles in breast cancer develop- modulate intracellular signaling via direct interaction with cell surface
ment. Laminin-111 (LM-111) is an important component of basement receptors such as receptor for hyaluronic acid mediated motility
membranes, secreted by normal breast myofibroblasts and maintains (RHAMM) and CD44 [64]. RHAMM promotes breast cancer cell migra-
epithelial polarity. Prolactin-induced maturation of breast epithelial tion and invasion and its expression is controlled by the Hippo pathway
cells is promoted by LM-111 [49,50]. In breast tumors, expression of [65]. RHAMM and CD44 form complexes with ERK in invasive breast
LM-111 is often lost and associates with changes in cell polarity [51]. cancer cell lines, which mediate cell motility [66]. Clinically, HA may
In three-dimensional cultures of breast cancer cells, LM-111 decreases be linked to highly aggressive breast cancer. HA levels are significantly
the expression of DNA methyl transferase-1 (DNMT1), preventing higher in serum of metastatic breast cancer patients compared to pa-
methylation of the E-cadherin promoter and therefore increasing its ex- tients with no signs of metastasis [67].
pression levels. This induces cell–cell adhesion and suggests that LM- HA is produced by hyaluronan synthases (HAS), which are found at
111 may function as an inhibitor of breast cancer dissemination [52]. the intracellular surface of the plasma membrane, and is cleaved by hy-
However, growing evidence indicates that other laminins, such as LM- aluronidases (HYAL) [64]. HAS2 activity has been shown to be regulated
332, LM-511 and laminins containing the alpha 4 subunit may promote post-translationally, where O-GlcNAcylation induces enzyme activity
tumor progression. LM-332 expression is associated with aggressive and phosphorylation by adenosine monophosphate-activated protein
breast cancers and cancer cell-derived LM-332 has been shown to pro- kinase (AMPK) mediates inhibition [68,69]. HAS function may play an
mote anchorage-independent survival through interaction with the important role in breast cancer progression since high levels of HAS in
α6β4 integrin receptor [53,54]. This effect is mediated by the Rho family primary tumors of breast cancer patients predict poor clinical outcome
GTPase RAC and activation of nuclear factor kappa-light-chain-enhanc- [70,71]. Thus, further investigation of HAS regulatory events may
er of activated B cells (NFκB) [53]. Moreover, LM-332 has been shown to provide novel means to inhibit the enzyme activity in the context of
induce migration and invasion of breast cancer cells via α3 integrin [55]. breast cancer. In line with this, downregulation of HAS2 by antisense
In human breast cancer samples, LM-332 expression was observed at mRNA suppresses mammary tumor growth and metastatic spread in a
the boundaries of normal breast and tumor tissue, which associated xenograft murine model [72]. Furthermore, overexpression of Has2 in
with high EMT activity [56]. Furthermore, co-culture of breast cancer the MMTV-Neu mouse mammary carcinoma model accelerates tumor
cells with primary fibroblasts from the mammary gland induced LM- growth by promoting stromal recruitment, angiogenesis and cancer
332 and integrin β4 expression, which promoted cell-resistance to cell-survival. [73]. HAS2 has been shown to be produced by metastatic
anoikis [57]. CSCs and a knockdown or inhibition of HAS2 expression by short hair-
Studies by Pouliot and colleagues have shown that LM-511 mediates pin RNA or 4-methylumbelliferone (4-MU) respectively impaired
adhesion, migration and invasion in vitro as well as metastasis in vivo bone metastatic outgrowth of breast cancer cells [70]. Interestingly,
via integrin interaction in experimental breast cancer models [58,59]. TGFβ stimulation of normal mammary epithelial cells induces HAS2 ex-
Interestingly, a positive feedback loop inducing a LM-511 matrix via pression, which can mediate EMT, a crucial process in mammary gland
the transcriptional coactivator TAZ in breast cancer cells has recently development and remodeling [74]. Moreover, evidence suggests that
been identified. LM-511 interacted with integrin α6β1 receptors in a HA polymer size may be of significant importance in breast cancer. In-
subpopulation of breast cancer cells with self-renewal and tumor- creased low molecular weight HA in serum of breast cancer patients is
initiating capabilities [60]. This interaction resulted in increased TAZ ac- particularly associated with poor prognosis and highly invasive breast
tivity and further up-regulation of LM-511, which enhanced the capac- cancer cells express increased levels of HYAL1 and HYAL2, indicating
ity of the cells to form mammospheres, enriched in stem cell-traits, that HA degradation may occur during disease progression [75]. The
in vitro and tumors in vivo [60]. The link to stem cell properties is in- several steps involved in HA production and maturation may provide
triguing and is in line with previous studies analyzing human embryon- different opportunities to target this molecule in breast cancer.
ic stem (ES) cells, where LM-511 promotes pluripotency [61]. In a recent
study, α4 laminin encoded by the LAMA4 gene and a subunit of LM-411 2.4.2. Versican
and LM-421, was shown to enhance clonal expansion of breast cancer Versican is a chondroitin sulfate proteoglycan (CSPG). Chondroitin
cells and integrin β1-dependent tumor re-initiation in multiple organs sulfates (CSs) are a group of sulfated GAGs composed of two alternating
in a mouse model for breast cancer [62]. LAMA4 expression was induced sugars, N-acetylgalactosamine and glucuronic acid. CSs are often bound
by the FOXQ1 transcription factor and analysis of clinical samples to protein cores, forming CSPGs, and play an important role in breast
showed that LAMA4 associated with poor outcome in breast cancer pa- cancer progression [76]. Versican expression has been observed in
tients [62]. human breast cancer lesions where it accumulates within the ECM of
peritumoral stroma and correlates with poor relapse-free survival in pa-
2.4. Glycosaminoglycans and proteoglycans tients [77,78]. In vitro experiments show that secreted factors from can-
cer cells induce the expression and secretion of versican by fibroblasts
Glycosaminoglycans (GAGs) are large, unbranched polysaccharide [78]. Versican is an important modulator of cellular behavior in breast
chains built by repeated disaccharide units. The presence of carboxyl cancer and has been shown to promote cancer cell-survival, tumor
and sulfate groups renders GAGs highly hydrophilic. This enables growth and bone metastasis when overexpressed in a mouse model
them to form porous gels that occupy large extracellular space and [79]. Interestingly, overexpression of versican can enhance self-
J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55 45

renewal and stem cell properties through epidermal growth factor re- architecture of the ECM. This structural organization promotes direc-
ceptor (EGFR) signaling [80]. Versican was shown to induce breast can- tional cancer cell migration and invasion [103]. Different lines of evi-
cer stem cell markers such as aldehyde dehydrogenase 1 (ALDH1), dence suggest that cancer cell-derived SDC-1 may also be relevant
CD44 and integrin-β1, to promote mammosphere and colony formation during cancer development. SDC-1 overexpression in cancer cells
in vitro and to fuel tumorigenesis in vivo [80]. leads to poorly cohesive and more invasive colonies when cells are
grown as 3D cultures, indicating that SDC-1 may promote invasiveness
2.4.3. Decorin and lumican in early stages of tumorigenesis [104]. In a second study, SDC-1 was
Decorin and lumican belong to the group of small leucine-rich pro- shown to mediate breast carcinoma cell-spreading in an integrin
teoglycans (SLRPs). These proteins contain leucine-rich repeats (LRRs) αvβ3-dependent manner, indicating a functional coupling of SDC-1
that bind collagen and are involved in fibril assembly, can sequester and αvβ3 integrin [105]. Interestingly, SDC-1 has been shown to pro-
growth factors and regulate cell signaling [81]. mote stem cell properties via regulation of the Wnt and IL-6/STAT-5
Decorin has emerged as an interesting breast tumor- and metastasis pathways [106].
suppressor [82]. In the healthy mammary gland, significant decorin ex- Glypican-1 (GPC1) expression is increased in breast tumor samples
pression can be observed while expression is reduced in breast cancer in comparison to normal breast tissues [107]. Downregulation of GPC1
[83–85]. Decorin can serve as an inhibitor of several receptor tyrosine in cancer cells can cause a decrease in the mitogenic response to
kinases. In breast cancer cells, decorin inhibits cell receptors of the heparin-binding growth factors, indicating that it might contribute to
ErbB family like the epidermal growth factor receptor (EGFR) and disease progression [107]. In contrast, glypican-3 (GPC3) is proposed
ErbB2, which are important promoters of breast cancer progression to be a tumor suppressor. Expression of GPC3 is silenced in breast can-
[86,87]. Decorin overexpression in breast cancer cells and consequential cer, at least partially due to hypermethylation of the GPC3 promoter
inactivation of ErbB2 leads to growth suppression in vitro via induction [108]. Overexpression of GPC3 in breast cancer cells significantly
of cell cycle regulator p21 [87]. This tumor-suppressive role was inhibits cell growth [108]. In a murine breast cancer model, ectopic ex-
also found to be relevant for lung metastatic spread in a breast cancer pression of the GPC3 gene was shown to abrogate tumor growth and
model, where decorin overexpression or systemic administration of re- lung metastatic ability [109]. GPC3 regulatory role involves a number
combinant decorin protein significantly reduced ErbB2 expression and of cellular functions. In vitro, overexpression of GPC3 sensitizes cells to
activation, causing an inhibition in mammary tumor growth and metas- serum starvation-induced apoptosis, delays spreading and reduces mo-
tasis [88–90]. Decorin has also been suggested to affect TGFβ signaling tility. Furthermore, GPC3 induces expression of E-cadherin, loss of
where cleaved decorin reduces the availability of activated TGFβ1 cyto- which is often associated with breast cancer progression [109]. Ectopic
kine, impeding breast cancer progression [91]. Interestingly, recent expression of GPC3 in a murine mammary carcinoma model inhibits
evidence indicates that in breast cancer cells, decorin can induce a the PI3K/Akt pathway and strongly induces p38 kinase activity,
state of mitophagy, which is a selected degradation of mitochondria resulting in increased apoptosis [110]. Together, evidence indicates
by autophagy [92]. This was shown to occur via decorin-dependent in- that GPC1 and GPC3 may act as a promoter and a suppressor of breast
duction of the mitochondrial protein and the putative tumor suppressor cancer, respectively.
mitostatin [92]. These insights into decorin's anti-tumoral and anti-
metastatic roles have also been validated clinically. Protein levels of 2.5. Matricellular proteins
decorin were shown to correlate with good prognosis in a cohort of
140 breast cancer patients [93]. Matricellular proteins are a group of structurally diverse ECM
Lumican expression has been observed within the stroma of breast glycoproteins that includes osteopontin, tenascins, periostin, SPARC,
tumors [85,94]. However, analysis of clinical samples from breast cancer thrombospondins and others. Matricellular proteins are expressed dur-
patients treated with endocrine therapy indicated that low lumican ex- ing embryonic development, but are highly regulated in the adult where
pression was associated with poor relapse-free and overall survival [93]. their expression is primarily associated with stem cell niches and tissues
Moreover, in a mouse model for metastatic breast cancer, ectopic lumican undergoing remodeling such as wound healing and inflammation [5,
expression impaired both mammary tumor growth and lung metastasis 111]. Most matricellular proteins bind fibronectin or collagen fibers
[95]. This indicates that, similar to decorin, lumican may serve as a and can modulate cell–matrix interactions. Many of these proteins
tumor-suppressor in breast cancer. However, the cellular and molecular can antagonize adhesive properties of other ECM proteins, generat-
details of its role in this context need further investigation. ing an intermediated state of adhesion [112]. The anti-adhesive
properties of matricellular proteins were used as a common feature
2.4.4. Syndecans and glypicans when the term was originally coined around this heterogeneous
Syndecans and glypicans are heparan sulfate proteoglycans (HSPGs) group of proteins [111]. Although matricellular proteins bind structural
that are found attached to the cell membrane. Whereas syndecans components of the ECM such as collagens, they are not thought to con-
are type I transmembrane proteins that incorporate up to five GAGs, tribute significantly to ECM structure. However, evidence indicates that
glypicans are anchored to the cell membrane by a glycosylphos- matricellular proteins serve an important role as cell regulators and
phatidylinositol (GPI) anchor [96]. modulators of signaling pathways [113,114]. During tumor progression,
Syndecan-1 (SDC-1) expression is consistently observed in the stro- cancer cells require dynamic cell adhesion attributes and in line with
ma of human and murine mammary tumors [97,98]. High expression of this, matricellular proteins are frequently highly expressed in tumors.
SDC-1 in the stroma of human breast tumors predicts poor overall Moreover, increased expression of matricellular proteins is commonly
patient survival [99]. SDC-1 expression is particularly linked to poor associated with metastatic spread and poor outcome in cancer patients
overall survival for patients treated with systemic chemotherapy [113]. Changes in cell adhesion significantly affect cellular motility, and
[100]. SDC-1 levels predict a reduced pathological response to systemic most matricellular proteins are linked to increased motility and invasive
cyclophosphamide–epirubicin neoadjuvant chemotherapy [101]. In cancer cell behavior. Importantly, a number of other cellular functions
vitro co-culture experiments have provided insights into SDC-1 mediat- have been shown to be modulated by matricellular proteins, such as
ed crosstalk between stromal cells and cancer cells. SDC-1 induction survival and growth under stressful conditions [115,116].
was observed in fibroblasts co-cultured with aggressive breast cancer
cells, but not when cultured with indolent cancer cells, and in turn fibro- 2.5.1. Osteopontin
blasts stimulated the growth of breast cancer cells in an SDC-1 depen- Osteopontin or secreted phosphoprotein 1 (SPP1) is a highly modi-
dent manner in vitro and in vivo [98,102]. Interestingly, fibroblast- fiable matricellular glycoprotein that has been linked to breast cancer
produced SDC-1 may contribute to the generation of organized fibrillar progression [117,118]. In normal mammary glands, SPP1 expression is
46 J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55

generally low, but is induced particularly during lactation and be required for normal mammary gland development [134]. However,
involution [119]. Transgenic mice expressing SPP1 in the mammary increasing evidence indicates that POSTN plays an important role in
gland exhibit increased proliferation and altered differentiation of breast cancer progression and metastasis. Overexpression of POSTN in
mammary epithelial cells [120]. While SPP1 expression alone is not suf- human breast cancer cells induced primary tumor growth and angio-
ficient to generate tumors, these results may indicate that SPP1 could genesis in a xenograft model by enhancing vascular endothelial growth
support progression of mammary tumors. Indeed, SPP1 expression has factor receptor 2 (VEGFR2) expression in endothelium [135]. Moreover,
been shown to promote metastatic ability in non-metastatic mammary POSTN was recently shown to interact with decorin and form intracellu-
tumors in a rat model [121]. Interestingly, in genetic mouse models, lar complexes that prevent decorin from being secreted to the extracel-
mammary tumors driven by expression of c-myc and v-Ha-ras onco- lular space [136]. Upon POSTN knockdown in invasive breast cancer
genes appear not to require SPP1 for tumor development, which may cells, decorin secretion is induced, leading to decreased motility and in-
indicate that SPP1 is either particularly important for later stages in vasiveness in vitro [136]. POSTN expression is higher in breast tumors
tumor progression and metastasis, or that it is dependent on a specific and breast cancer cell lines compared to normal human breast tissues
oncogenic context [122]. SPP1 expression is linked to increased metas- [137,138]. In a murine xenograft model, mice bearing bone metastasis
tasis in mouse models, where breast cancer cells with increased ability showed high expression of POSTN in the stroma surrounding metastatic
to metastasize to bones exhibited a significantly higher SPP1 expression tumors and high POSTN levels in the plasma [139]. POSTN has been
when compared to the pool of parental cells [123]. SPP1 has also been shown to be a key ECM component of the metastatic niche by
suggested to be a useful biomarker for breast cancer progression in supporting the growth of metastasis-initiating cells with stem-like
humans. Analysis of SPP1 expression in breast cancer samples from a properties [116]. Although Postn null mice developed mammary tumors
cohort of lymph node-negative patients showed that SPP1 expression driven by a polyoma middle T (PyMT) transgene, ablation of Postn in
in cancer cells is associated with poor relapse-free and overall survival the stroma of these mice significantly impaired lung metastatic ability
[124]. Moreover, plasma levels of SPP1 quantified by enzyme-linked im- of the tumors. This effect was linked to enhanced Wnt signaling, stimu-
munosorbent assay (ELISA) significantly correlate with increased tumor lating metastasis-initiating capacity of mammary cancer cells [116]. In
burden and decreased survival in breast cancer patients [125]. High metastasis, CAFs and sprouting endothelial cells have been identified
SPP1 levels in serum may reflect SPP1 expression in tumors of different as sources of POSTN [116,140]. Moreover, POSTN has been shown to
locations; however, evidence from mouse models indicates that SPP1 in be induced in a CSC population expressing high CD44 and low CD24 sur-
serum may have functional roles involving mobilization of stromal cells face markers and its downregulation by siRNA sensitizes breast CSCs to
from bone marrow [126]. chemotherapeutic drugs [141]. Overexpression of POSTN in mammary
epithelial cells and breast cancer cells enhanced stem cell properties
2.5.2. Tenascin C and mesenchymal traits and promoted tumor growth and metastatic
Tenascin C (TNC) is a large hexameric matricellular glycoprotein progression in breast cancer cells [142]. POSTN expression may predict
able to interact with cell surface receptors and other ECM proteins. In poor prognosis and response to primary treatment of breast cancer pa-
the mammary gland, TNC expression is associated with mammary tients [141]. Interestingly, POSTN was shown to bind TNC, thus incorpo-
gland involution and breast cancer development [127]. Growing evi- rating TNC into ECM composed of collagen type I and fibronectin [143].
dence indicates that TNC expression in breast tumors is a predictor of This suggests a possible collaboration between TNC and POSTN in
metastatic relapse and poor overall survival [115,128,129]. Experimen- forming the metastatic niche, where POSTN presents Wnt ligands to
tal analyses confirm this link and provide insight into the functional role cancer cells and TNC regulates the ability of cancer cells to respond to
of TNC in breast cancer progression. In breast cancer cells, TNC is Wnt [144].
expressed as a part of a gene signature that associates with metastasis
to lungs and was TNC shown to be regulated by the microRNA 2.5.4. SPARC
miR335 in this context [17,130]. Metastatic breast cancer cells with Secreted Protein, Acidic and Rich in Cysteine (SPARC) plays an im-
high propensity to colonize the lung lose miR335 expression, leading portant role in matrix remodeling and cell motility. SPARC transcript
to upregulation of TNC, which is an essential component of the metasta- levels are higher in breast tumors compared to normal breast tissue
tic niche [17,115]. Knockdown of cancer cell-derived TNC impaired the [145]. In a mouse model in which breast cancer cells were selected for
ability of metastatic breast cancer cells to colonize lungs and bones, in- increased proficiency to colonize the lungs, metastatic cancer cells
dicating a requirement for autocrine TNC in metastasis [115]. TNC- expressed significantly higher SPARC levels compared to non-selected
mediated lung metastasis was promoted by increased survival and met- parental cells [130]. Moreover, analysis of tissue samples from breast
astatic fitness of disseminated cancer cells induced by the Wnt and cancer patients indicates that SPARC expression correlates with breast
Notch pathways [115]. Autocrine TNC is initially required for cancer cancer progression. SPARC is increased in breast tumors compared to
cells to colonize the distant organ, however, stromal-derived TNC also normal breast tissues and further increased in tumors from patients
supports metastatic colonization. Murine mammary carcinoma cells im- with high grade, node-positive breast cancer [145]. Expression of
planted into mammary fat pads of TNC knockout mice generated signif- SPARC is also linked to poor clinical outcome, correlating with increased
icantly less lung metastases compared to control mice [131]. Whereas recurrence of early breast tumors and poor overall survival in patients
cancer cell-derived TNC is required for the initial steps of metastatic col- with invasive breast cancer. [146,147]. Interestingly, SPARC mRNA
onization, it is redundant at later time-points, when the activated tumor levels in breast cancer tissues are inversely correlated with estrogen re-
stroma becomes a significant source of TNC [115]. Therefore, TNC se- ceptor (ER) expression [148]. This underscores the link between SPARC
creted from different sources within the tumor microenvironment pro- and aggressive breast cancer, since tumors expressing ER frequently ex-
motes metastatic progression in breast cancer. hibit significant differentiation and less aggressive properties. More-
over, SPARC production was shown to be regulated by integrin β4-
2.5.3. Periostin mediated signaling via induction of target of rapamycin (TOR) signaling
Periostin (POSTN) is a homodimeric matrix protein that plays an im- and downregulation of miR-29 that directly targets SPARC [149]. Func-
portant role in bone, dental and cardiac development as well as in tissue tionally, SPARC was shown to be both sufficient and required for devel-
repair in the adult [132]. POSTN is known to interact with αvβ3, αvβ5, opment of lung metastasis in a xenograft mouse model [130].
and α6β4 integrin receptors and to modulate intracellular tyrosine ki-
nase signaling such as PI3K/Akt and focal adhesion kinase (FAK) [133]. 2.5.5. Thrombospondins
Although POSTN expression is present in the end buds of mammary The thrombospondin (THBS) family is comprised of calcium binding
glands [116], a study on Postn null mice suggests that Postn might not glycoproteins that play a regulatory role in wound healing and
J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55 47

angiogenesis. THBS1 and 2 inhibit angiogenesis by binding receptor promotion of a more aggressive phenotype in cancer cells. Released
CD36 on endothelial cells and inducing apoptosis [150]. In breast cancer SDC-1 promotes proliferation of breast cancer cells via fibroblast growth
models, THBS1 antiangiogenic function leads to inhibition of primary factor-2 (FGF2) depending mechanism [168]. Moreover, shed SDC-1
tumor growth [151]. However, evidence suggests that THBS response from primary breast tumors may promote distal osteolytic processes
by cancer cells or non-endothelial stroma may result in promotion of in bone metastasis by enhancing osteoclast differentiation [169]. High
cancer progression and metastasis. THBS1 can induce cancer cell inva- MMP-2 plasma levels and expression in breast tumors predicts poor
sion via activation of TGFβ and upregulation of the urokinase plasmino- clinical outcome in breast cancer patients [170,171]. In transgenic
gen activator system [152,153]. Moreover, studies in mouse models mouse models, ectopic MMP-3 or MMP-14 expression targeted to the
have shown that THBS1 and 2 indeed promote metastatic colonization mammary gland can lead to fibrosis, dysplasia and even carcinogenesis,
of distant organs [151,154]. THBS2 expression by cancer cells promotes underscoring the inductive properties of these enzymes [172,173].
stromal activation in secondary organs which fuels metastatic coloniza-
tion [154]. THBS1 expression in tumor samples or high levels in plasma 3.2. Heparanase
from breast cancer patients are associated with poor relapse- free
survival [155,156]. Further studies are required to understand the dif- A growing body of evidence points to heparanase as an important
ferent roles of THBS during breast cancer progression and address the ECM remodeling enzyme involved in breast cancer progression.
potentially divergent properties of primary tumors and metastasis. Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate
chains, generating low molecular weight fragments [159]. In normal
3. ECM remodeling mammary gland, heparanase is expressed at the edges of invading epi-
thelium and is associated with expression of MMP-14 during branching
ECM changes during tissue regeneration and cancer are not limited morphogenesis of the gland [174]. Overexpression of heparanase,
to core-ECM components, but also include remodeling enzymes [157]. targeted to the mammary gland, enhances invasive branching of mam-
ECM modifying enzymes such as matrix metalloproteinases, mary epithelia in mouse models [174,175]. The link between
heparanase, cathepsins, urokinase plasminogen activator and heparanase activity and aggressiveness of breast cancer was first
crosslinking enzymes of the lysyl oxidase family are often aberrantly described by Vlodavsky and colleagues [176]. Subsequently, several
upregulated in breast tumors and contribute significantly to breast can- studies have demonstrated the direct implication of heparanase in me-
cer progression and metastasis [5,158,159]. These enzymes can modify diating breast cancer progression. In mouse models, heparanase has
the ECM in distinct ways. The enzymes can generate paths of least resis- been shown to promote neovascularization and mammary tumor
tance and facilitate cancer cell invasion and migration. Moreover, they growth [177,178]. Evidence indicates that this may be at least in part
can directly affect the biological properties and function of ECM compo- mediated by heparanase induction of SDC-1 [179]. Heparanase expres-
nents by exposing cryptic sites, releasing ECM-bound growth factors or sion is significantly associated with spread to the lymph nodes in breast
soluble domains of ECM proteins. Finally, remodeling enzymes may cancer patients with high-grade tumors [180]. Interestingly, studies in
change the physical properties of ECM structures for instance by mouse models show that heparanase expression in breast cancer
crosslinking [24]. Many of the functions facilitated by ECM remodeling cells with low metastatic ability can significantly increase metastatic
enzymes are crucial for the progression of breast cancer and develop- potential [175]. Moreover, miR1258 was shown to directly repress
ment of metastasis. heparanase and inhibit metastasis to the brain in breast cancer models
[181]. Importantly, evidence also indicates that heparanase is involved
3.1. Matrix metalloproteinases in resistance to therapy [182,183].

Of the large family of matrix metalloproteinases (MMPs), MMP-2, 3.3. Cathepsins


-3, -9 and -14 are overexpressed both during mammary gland involu-
tion and in breast cancer [5,11]. MMP-2 and MMP-3 are important Cathepsins are a family of lysosomal proteases, of which several fam-
ECM remodeling enzymes in the normal mammary gland, controlling ily members have been associated with mammary gland remodeling
branching during morphogenesis [160]. In cancer, invasion through and breast cancer progression [157,184,185]. Experimental evidence
the basement membrane is a required step for metastatic spread and indicates that cathepsin B and -K, for example, play a major role in
MMP-2 and MMP-9 may play an important role in this process by breast cancer. In a genetic mouse model for mammary carcinoma,
degrading collagen type IV [161]. ablation of cathepsin B significantly impaired the formation of invasive
Proteolysis of collagen is an important invasion mechanism that ductal carcinoma and lung metastasis [186]. In line with this, overex-
alters biomechanical ECM characteristics. Pericellular collagenolysis pression of cathepsin B accelerated tumor growth and promoted lung
mediated by the membrane-bound protease MMP-14 on the surface metastatic progression in mice [187]. Inhibition of cathepsin B by a
of breast cancer cells is of major importance during cell migration and highly selective inhibitor in human breast cancer cells reduced collagen
invasion [162]. MMP-14 is particularly important for collective migra- type IV degradation and invasion [188]. Whereas cathepsin B is impor-
tion, where the tip cell of a polarized multicellular mass produces tant for lung metastasis, the protease also promotes metastasis to other
MMP-14 and degrades interstitial collagens to form a track which is sites. Cathepsin B was shown to mediate metastasis of murine mamma-
widened by following cells within the cell mass and facilitates invasion ry cancer cells to bones, where inhibition by interference RNA or by a
[162,163]. Moreover, in mammary epithelial cells and breast cancer small molecule inhibitor, significantly reduced bone metastatic burden
cells, MMP-2 was shown to induce invasive behavior by cleaving the in mice [189]. Cathepsin K, which is normally expressed specifically by
gamma 2 chain of LM-332, exposing a cryptic pro-migratory site con- osteoclasts and is involved in bone resorption, is also produced by breast
taining EGF-like repeats [164]. The liberated LM-332 fragment can cancer cells [190]. Selective inhibition of cathepsin K in pre-clinical mu-
bind EGFR, mediating MAPK signaling which promotes cell migration rine models, reduces osteolysis induced by breast cancer cells and in-
[164]. Interestingly, MAPK activation further induces MMP-2 expres- hibits metastatic colonization of the bone [191,192].
sion, generating a positive feed-back loop. This pro-migratory feedback
loop is additionally induced by the membrane-bound MMP-14, which is 3.4. Urokinase plasminogen activator
an important activator of MMP-2 and independently releases the
gamma 2 chain fragment from LM-332 [165,166]. The urokinase plasminogen activator (uPA) is a serine protease that
MMP-14 has also been shown to mediate SDC-1 shedding from the cleaves the inactive proenzyme plasminogen into active plasmin, lead-
surface of mammary CAFs [167]. This may be important for the ing to ECM degradation and remodeling [193]. In the mouse mammary
48 J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55

gland, uPA expression is significantly induced during involution [194]. 4. Therapeutic opportunities
Furthermore, uPA is consistently expressed in breast cancer and is par-
ticularly associated with invasive and metastatic tumors [195,196]. A Growing insights from experimental studies on the biological roles
number of studies indicate that uPA expression predicts poor clinical of the ECM in breast cancer suggest that ECM components and ECM-
outcome. Pooled analysis of over 8000 breast cancer patients from 17 mediated functions may include promising therapeutic targets. Interfer-
studies showed that high uPA levels predict poor relapse-free and over- ing with the function of breast cancer ECM can be achieved by a number
all survival [197]. of means. Several chemicals and biologics modulating cancer ECM
are under investigation as putative treatments against breast cancer
3.5. Lysyl oxidases (Table 1).
Inhibition of ECM components that promote tumor progression and
The family of lysyl oxidases (LOXs) is composed of enzymes that can metastasis may be an appealing strategy against breast cancer. A plausi-
promote crosslinking of ECM components such as collagens and elastin ble approach would be to inhibit the synthesis of those ECM compo-
[8]. ECM crosslinking leads to an increased matrix stiffness, which has nents that have a pro-tumorigenic function. Pre-clinical studies in
been associated with tumor progression in breast cancer [24]. In a animal models have demonstrated that this is conceivable and could
mouse model of breast cancer development, expression of LOX was in- be translated into clinical practice. An example of this is the use of 4-
creased in both premalignant and malignant tumor lesions when com- methylumbelliferone (MU) to inhibit the synthesis of the tumor-
pared to normal mammary tissue. LOX activity induces crosslinking of promoting GAG HA. Administration of MU to mice with growing bone
collagen fibers, leading to increased stiffness, that promotes PI3K activ- metastases inhibited HAS2 expression and subsequently HA synthesis,
ity through focal adhesions [24]. Inhibition of LOX results in decreased which resulted in reduced bone metastatic outgrowth [200].
tumor incidence and size, reduces tissue fibrosis and causes a delay in Direct neutralization of pro-tumorigenic ECM components is an ap-
tumor progression [24]. Moreover, cancer cell-derived LOX promotes pealing approach, but may be challenging due to their frequent
metastatic progression by modifying the ECM of the metastatic niche multidomain structure. However, recent studies in pre-clinical models
[16,198,199]. In breast cancer patients, elevated LOX expression corre- are revealing encouraging results, where ECM components could be
lates with metastatic disease and poor overall survival [198]. blocked directly via targeted peptides, neutralizing antibodies or DNA

Table 1
Examples of therapeutic agents used in pre-clinical or clinical studies that target pro-tumorigenic/metastatic ECM components or mimic tumor-suppressive ECM cues in breast cancer.

Antagonists

Target protein Therapeutic Type Effect Reference


agent

HAS2 MU Small molecule inhibitor Downregulation of HAS2 and HA synthesis; reduced bone metastasis in mice [200]
Periostin PN1-Ab Blocking antibody Reduced mammary tumor growth and lung metastasis and improved survival in a [201]
murine model; reduced migration in vitro
PNDA-3 DNA aptamer Reduced mammary tumor growth and lung-, liver-, spleen- and lymph node [202]
metastasis in a mouse model; inhibition of Src activity; reduced adhesion, migration
and invasion
Tenascin-C F16-IL2 IL-2 coupled antibody Reduced primary tumor growth; synergistic effect in combination with chemotherapy [205]
in murine xenografts
Syndecan-1 131I-labeled B-B4 Radio-labeled antibody Reduced mammary tumor growth, improved survival of mice [206]
β1 integrin AIIB2 Blocking antibody Decreased tumor formation and growth in mice; increased apoptosis [208]
α5β1/αvβ3 integrin ATN-161 Inhibitory peptide Reduced mammary tumor growth and bone metastasis in murine models; decreased [209]
p-MAPK, and cell proliferation in mouse mammary tumors
αvβ3 integrin S247 Small molecule antagonist Reduced bone metastasis in mice; reduced adhesion and invasion in vitro [210]
PSK1404 Non-peptide antagonist Reduced bone metastasis in mice [211]
Intetumumab Blocking antibody Decreased brain metastasis and increased survival in rats [212]
αvβ3/αvβ5 integrin Cilengitide Inhibitory peptide Reduced bone metastatic growth in a rat model [213]
LOX BAPN Small molecule inhibitor Increased tumor latency, reduced tumor growth; reduced matrix crosslinking in a [24]
D8746 Blocking antibody mouse model
Heparanase PG545 Small molecule inhibitor Reduced tumor growth and inhibition of angiogenesis in a mouse xenograft model [221]
Cathepsin B CA-074 Small molecule inhibitor Reduced tumor growth, lung and bone metastasis in mice [189]
Cathepsin K AFG495 Small molecule inhibitor Reduced bone metastasis in a mouse model [191]
L-235 Small molecule inhibitor Reduced bone metastasis in rats [192]
Odanacatib Small molecule inhibitor Suppression of bone resorption in women with breast cancer metastasis in bone [222]*
MMP-14 DX-2400 Blocking antibody Inhibition of tumor growth in a murine model, synergistic effect in combination with [225]
radiotherapy; increased iNOS levels and tumor perfusion; reduced hypoxia, TGFβ and
SMAD2/3 signaling

Agonists

Protein Therapeutic agent Type Effect Reference

Endostatin Endostatin Recombinant peptide Reduced mammary tumor growth in rats [227]
rhES Recombinant peptide Reduced mammary tumor growth in mice [228]
Endostar Recombinant peptide Improved therapy response in breast cancer patients [230]*
Decorin Decorin core Recombinant protein Reduced tumor growth and metabolism; reduction of ErbB2 levels; prevention of lung [88]
metastasis in a mouse model
Decorin Recombinant protein Reduced tumor growth and metastases; downregulation of ErbB2 levels and activity [89]
in a rat model

HAS2, hyaluronan synthase 2; MU, 4-methylumbelliferone; HA, hyaluronan; PNDA-3, periostin-binding DNA aptamer 3; IL-2, interleukin 2; p-MAPK, phosphorylated mitogen-activated
protein kinase; LOX, lysyl oxidase; BAPN, β-aminopropionitrile; MMP-14, matrix metalloproteinase-14; iNOS, inducible nitric oxide synthase; TGFβ, transforming growth factor β;
SMAD2/3, SMAD family member 2/3; ErbB2, receptor tyrosine kinase erbB2.
⁎ Clinical trials.
J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55 49

aptamers. For example, treatment of tumor-bearing mice with PN1-Ab, inhibitors against cancer, including breast malignancies, may provide
a neutralizing antibody against POSTN, impaired mammary tumor alternative means to regulate ECM-mediated functions [219].
growth and lung metastasis [201]. Similarly, a DNA aptamer also It has long been recognized that mammary tissue density correlates
targeting POSTN (PNDA-3) blocked its binding to integrins αvβ3 and with high breast cancer risk [220]. We discussed earlier the important
αvβ5 and inhibited POSTN-induced downstream signaling pathways. role that collagen crosslinking and ECM remodeling enzymes play in
This resulted in decreased adhesion and migration in vitro, and im- stiff fibrotic tissues, promoting breast cancer progression and metastatic
paired tumor growth and metastasis in vivo [202]. spread. Antifibrotic therapies directed against ECM remodeling en-
Specific ECM components are expressed in actively invading regions zymes might be a good cancer-treatment strategy. For example, inhibi-
of tumors and can be used as markers of these regions. Therefore, anti- tion of collagen crosslinking enzymes such as the LOX family leads to
bodies against remodeled ECM may direct bioactive inhibitory cues or impaired tumor growth and metastasis [24]. LOX inhibitors are current-
radioactivity to relevant parts of the tumor. This approach would en- ly in development for clinical use [220].
hance the effect of radiation, chemotherapy or targeted therapy by con- As previously described, heparanase plays an important role in the
centrating the radioisotope, drugs or tumor suppressive biologics at progression of breast malignancies and experimental evidence indicates
active sites within the tumor, while minimizing their distribution in that its inhibition may constrain tumor growth and metastatic spread.
healthy tissues [203]. Matricellular proteins might be promising targets Therefore, selective inhibitors against heparanase enzymatic activity
for this type of therapeutic strategy since their levels are very low in might be a viable tool to treat breast tumors. In fact, administration of
normal adult tissues, but they are highly expressed in cancer. Indeed, PG545, a heparanase inhibitor, causes a marked impairment of tumor
studies in colon cancer and glioblastoma models show a selective accu- growth and metastasis in pre-clinical mouse models [221].
mulation of radio-labeled anti-TNC antibodies in xenograft tumors [203, Protease inhibition is another promising strategy to battle
204]. This could be a plausible strategy for breast cancer alike, due to the breast cancer. In pre-clinical models, blocking uPA has been shown to
high immunoreactivity of TNC observed in human and experimental be an effective treatment to impede mammary tumor growth and me-
breast tumors [115,128]. Notably, interleukin-2 (IL-2)-coupled antibody tastasis [195]. Currently, a number of uPA inhibitors are undergoing
(termed F16-IL2) against a specific isoform of TNC, which is present in clinical trials. Inhibition of cathepsins has also been shown to be encour-
tumors but virtually absent in normal tissue, has been shown to inhibit aging. In a mouse model, CA-074, a selective cathepsin B inhibitor, re-
growth of mammary tumors in mice [205]. Strikingly, combining the duced both bone and lung metastatic burden [189]. Furthermore,
administration of F16-IL2 antibody with chemotherapy showed a experimental inhibition of cathepsin K likewise showed an efficient de-
marked synergistic inhibitory effect [205]. Targeting other cancer-asso- crease in breast cancer growth in the bones of tumor-bearing animals
ciated ECM molecules has also shown promising results in animal [191,192]. In a clinical trial that included 43 women with breast cancer
models. In a pre-clinical study using a xenograft mouse model, a metastasis in bone, the administration of the cathepsin K inhibitor
radio-labeled anti-SDC-1 antibody was specifically taken up by tumors odanacatib suppressed bone resorption that is commonly associated
and mice treated with this radioimmunotherapy showed a significantly with metastatic skeletal lesions [222].
decreased tumor growth [206]. More than two decades ago, MMPs were noted as promising targets
Blocking receptors that interact with components of the ECM may against cancer [223]. Experimental evidence indicates that MMPs
also be a way to treat metastatic breast cancers. The interaction between play an important role in cancer progression and metastasis, which
integrins and ECM leads to recruitment and activation of intracellular prompted the development of MMP inhibitors (MPIs) and their transla-
signaling proteins, initiating signal transduction cascades and promot- tion into clinical use. Over 50 MPIs were pursued, but all clinical trials
ing cancer cell migration, proliferation and survival [207]. Therefore, failed. These surprising and disappointing results may have a number
integrins represent an interesting target for cancer therapies. For in- of explanations such as poor drug bioavailability, high toxicity, low se-
stance, targeting β1 integrin with an inhibitory antibody reduced lectivity or lack of efficacy [223]. New generation MPIs with higher se-
growth and induced apoptosis of human breast cancer cells in vitro lectivity against pro-metastatic MMPs are currently being developed
and in vivo [208]. In a pre-clinical mouse model, treatment with ATN- and tested in pre-clinical models of cancer [224]. For example, the
161, a 5-mer capped peptide that binds to integrins α5β1 and αvβ3, re- MMP-14 blocking antibody DX-2400 has recently been tested in a mu-
sulted in decreased tumor growth and inhibited bone metastasis [209]. rine model of breast cancer, where it inhibited primary tumor growth
Administration of selective inhibitors against integrin αvβ3 impaired when administered alone and further impaired the growth when com-
bone metastatic outgrowth in xenograft mouse models [210,211]. bined with radiotherapy [225]. Future studies will reveal if the new gen-
Intetumumab, a monoclonal antibody blocking integrin αvβ3, de- eration MPIs turns out to be more successful then older generations.
creased metastasis and increased survival in a rat model for breast can- Finally, certain ECM cues are tumor- and metastasis-suppressive and
cer metastasis to brain [212]. Similarly in rats, a reduction in bone thus potentiating their biological effect might be a viable therapeutic
metastases was observed upon administration of cilengitide, an integrin possibility against breast cancer. Promising results have been obtained
αvβ3/αvβ5 inhibitor [213]. by administering endostatin to both animal breast cancer models and
Given that ECM components can induce signals in breast cancer cells human patients. Endostatin is a soluble naturally occurring angiostatic
that promote their metastatic fitness, it is reasonable to focus attention and tumor-suppressive ECM cue derived from the cleavage of collagen
on ECM-activated intracellular signaling cascades and their subsequent XVIII-α1 and has been shown to inhibit receptor tyrosine kinase
downstream transcriptional output as targets against breast cancer. (RTK) activity [226]. In rodent mammary carcinoma models, adminis-
ECM cues activate Src–FAK via integrin receptors, which can trigger a tration of endostatin as a recombinant peptide inhibited breast tumor
range of cellular signaling cascades resulting in altered cell proliferation, growth [227,228]. In a pre-clinical mouse model, the combined treat-
angiogenesis, invasion and metastasis [214,215]. Src family members ment with recombinant endostatin and paclitaxel–cisplatin therapy
are non-receptor tyrosine kinases that have been proposed as molecular inhibited growth of mammary tumor xenografts to a higher degree
targets against cancer [215]. Metastatic breast cancer cells depend on than either one of the two therapies alone [229]. These results were con-
Src to survive in the bone during tumor latency [216]. Targeting Src by firmed in a clinical trial on 68 breast cancer patients, where neoadjuvant
small molecule inhibitors is thus a promising opportunity to prevent co-treatment with recombinant endostatin (endostar) and chemother-
metastatic progression of breast cancers. Indeed, clinical trials using apy resulted in improved tumor response, compared to chemotherapy
Src inhibitors have been initiated against breast cancer [217]. Inhibition alone, without increasing appreciably side effects in patients [230]. A
of FAK represents another opportunity to suppress ECM-induced second clinical trial using endostar in patients with metastatic breast
signaling. In experimental models, downregulation of FAK in breast cancer is currently ongoing. Decorin is another tumor-suppressive
cancer cells results in decreased tumor growth [218]. The use of FAK ECM cue that has been demonstrated to inhibit breast cancer growth
50 J. Insua-Rodríguez, T. Oskarsson / Advanced Drug Delivery Reviews 97 (2016) 41–55

in pre-clinical models. Systemic administration of recombinant decorin may also serve as targets for breast cancer intervention. The physiolog-
in animal models bearing mammary tumors prevented metastatic ical context of a growing tumor, particularly in secondary organs as me-
spread [88,89]. All these studies accentuate the possibility of using tastasis, is of great importance when developing treatment directed
tumor- suppressive ECM components against breast cancer, either as against ECM in cancer. This is because ECM is exceedingly context-de-
single agents or in combination with standard systemic therapies. pendent and an understanding of ECM function in the appropriate con-
text improves the prospects of revealing applicable drug targets. With
5. Concluding remarks this in mind, it is essential to increase our knowledge of ECM dynamics
and function in the context of cancer progression and metastasis. This
Major changes are observed in the ECM of advancing breast cancer, includes characterization of distinct isoforms of matrix components,
involving both the induction of tumor-promoting ECM components since many ECM proteins have several different splice variants or are
and loss of tumor-suppressive ECM. Functional analyses in animal modified post-translationally, some of which may be tumor specific.
models indicate that cancer-associated matrix proteins affect several This can increase the accuracy of targeted therapy towards malignant
cellular processes. For instance, breast cancer cells rely on certain ECM tissue while minimizing collateral damage of healthy tissue. Moreover,
components and ECM-mediated signals in order to survive under envi- certain ECM components such as matricellular proteins are essentially
ronmental stress confronted at different stages of breast cancer progres- absent in healthy adult tissues and strongly upregulated in breast malig-
sion and metastasis. Therefore, inhibiting these particular matrix nancies. The contextual cues and physical aspects that are unique to
components or downstream functions may expose vulnerabilities in breast cancer tissues may prove to be valuable as targets. Increased un-
cancer cells that can contribute to treatment efficacy. Importantly, derstanding of the interactions between cancer cells and the ECM is
ECM function can be modulated by a number of mechanisms (Fig. 2). likely to develop into further therapeutic options that can be translated
The production of ECM components as well as the activity of ECM- into future clinical practice.
modifying enzymes may be promising targets. Furthermore, direct neu-
tralization of ECM functional domains or ECM binding receptors provide Acknowledgments
additional opportunities to prevent pro-tumorigenic ECM activity. Fi-
nally, the signaling pathways downstream of ECM binding receptors We would like to thank M. Pein and K. Decker for critical reading of
the manuscript and helpful comments. T.O. is supported by the Marie
Curie CIG Actions (CIG334563) and the Dietmar Hopp Foundation.

2
3
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