NEWS & VIEWS

C O L O R E C TA L C A N C E R of Fusobacterium (Fusobacterium necro­

phorum and F. nucleatum) isolates cultured

Hand‑in‑hand — colorectal
from paired primary and metastatic tumours
revealed >99.9% average nucleotide identity,
suggesting that the metastasis-associated

cancer metastasizes Fusobacterium originated from primary CRC.

Moreover, RNA sequencing and b ­ acterial
16S ribosomal RNA gene sequencing identi­
with microorganisms fied additional bacteria, including Bacter­
oides fragilis, Bacteroides thetaiotao­micron,
Prevotella intermedia and Selenomonas sputi­
Ye Yang and Christian Jobin gena, which were also shared by paired pri­
Increased relative abundance of Fusobacterium species contributes to the mary and metastatic tumours, suggesting the
presence of a metastasis-associated micro­
difference in intestinal bacterial composition between healthy individuals biota10. Similar dominant bacterial genera
and patients with colorectal cancer (CRC). A new study now reveals that live were found in Fusobacterium-positive paired
Fusobacterium originating from primary CRC associate with liver metastasis, primary and metastatic tumours, with the
same Fusobacterium species (F. necrophorum
suggesting a potentially important function for this bacterial genus in
or F. nucleatum) present at a ­similar rela­
metastatic tumour growth. tive abundance. By contrast, little similarity
Refers to Bullman, S. et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science in the microbiota was observed between
358, 1443–1448 (2017) Fusobacterium-negative primary and metasta­
ses tumour pairs. Analyses of published
data from a different cohort of 430 primary
The immunomodulatory and metabolic these findings, a new study by Bullman et al.10 CRCs (The Cancer Genome Atlas) revealed
activities of the gut microbiota profoundly has greatly advanced our understanding of enrichment of Bacteroides, Prevotella and
influence the balance between health and the effect of Fusobacterium on late-stage CRC Selenomonas in primary CRCs with high
disease, and disruption of host–­microbiota by showing that Fusobacterium persist dur­ Fusobacterium load (>1% relative abun­
interactions are associated with numer­ ing CRC m ­ etastasis and promote m ­ etastatic dance)10. These observations suggest that
ous pathologies including colorectal cancer tumour growth. Fusobacterium are likely accompanied by other
(CRC)1. Among the differentially represented primary CRC-associated m ­ icroorganisms
bacteria in CRC, Fusobacterium (predomin­ ­during metastasis.
antly Fusobacterium nucleatum) have been Their findings suggest RNA in situ hybridization detected invasive
found across numerous independent studies F. nucleatum in colon cancer-like cells of pri­
that bacteria, at least in the
to be enriched in tumours compared with mary tumours and liver metastases, suggesting
normal tissues2. The mechanisms by which CRC setting, are an integral that the bacterium likely spreads within pri­
F. nucleatum influences carcinogenesis are component of metastasis... mary CRC cells. By comparison, F. nucleatum
surprisingly varied, and include activation were exclusively located in biofilms in normal
of E‑cadherin–β‑catenin signalling via the adjacent colonic mucosa and were not detected
adhesion protein FadA3, establishment of a The authors of the latest study found that, in residual liver parenchyma. The authors then
pro-tumorigenic microenvironment4, inhib­ of 11 samples of paired fresh-frozen primary investigated whether Fusobacterium could per­
ition of antitumour immunity via the Fap2– colorectal tumours and liver metastases, sist through metastasis by testing their associ­
TIGIT (T-cell immunoreceptor with Ig and 9 primary tumours and 7 metastases con­ ation with CRC patient-derived xenografts
ITIM domains) interaction5, upregulation tained Fusobacterium DNA when examined (PDXs) in nude mice. Interestingly, the pres­
of microRNA‑21 to enhance cancer cell pro­ by qPCR. Notably, Fusobacterium-positive ence of Fusobacterium strongly correlated with
liferation and invasion6 and stimulation of liver metastases were universally derived from success­ful PDX generation. Of the 13 primary
cancer cell autophagy to promote resistance Fusobacterium-positive primary tumours, and CRCs tested, only Fusobacterium-positive
to chemotherapy7. However, the observations none of the Fusobacterium-negative primary and none of the Fusobacterium‑negative
that F. nucleatum preferentially colonizes tumours were associated with Fusobacterium- tumours could establish PDXs. By culturing
CRC over normal colon tissue 8 and that positive liver metastases. The same corre­ and sequencing analyses, the authors found
Fusobacterium are present at very low abun­ lations were observed in a different cohort that F. nucleatum, together with other anaer­
dance in cancer-paired normal colonic tissue9 consisting of 101 formalin-fixed paraffin-­ obes including B. fragilis and S. sputigena, were
suggest that these bacteria are more relevant to embedded colorectal carcinomas and paired stably associated with PDXs after multiple
CRC progression than initiation. In line with liver metastases. Whole-genome sequencing ­passages in mice.

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NEWS & VIEWS

CRC Primary colorectal cancer Liver metastasis modulate cancer cell activities at early stages
cells of metastasis, such as during escape from the
primary tumour, intravasation and survival
in the circulation is worth further investi­
gation. Finally, given the presence of other
metastasis-associated bacteria (Bacteroides,
Prevotella and Selenomonas), it is important to
determine how these microorganisms affect
Fusobacterium ­metastatic tumour growth.
↓ Tumour
growth
Although Fusobacterium are unlikely to
Fusobacterium-killing be a driver of CRC, their clinical importance
metronidazole
should not be underestimated. Through their
roles in chemoresistance7 and metastasis10,
Fusobacterium, particularly F. nucleatum,
↑ Tumour along with their associated activities might
growth represent novel therapeutic targets to improve
Patient-derived
xenograft outcomes in patients with CRC.

Fusobacterium-sparing Ye Yang and Christian Jobin are at the Department of

erythromycin Medicine, University of Florida, 2033 Mowry Road,
Gainesville, Florida 32611, USA; Christian Jobin is also
Figure 1 | Fusobacterium translocate with primary colorectal
Nature Reviews cancer cells to the&liver
| Gastroenterology Hepatology at the Department of Infectious Diseases and
and promote patient-derived xenograft tumour growth. Bullman et al.10 showed that the same Immunology and the Department of Anatomy and Cell
Fusobacterium species were present in paired primary and metastatic tumour samples from patients Biology at the University of Florida
with colorectal cancer (CRC) and that the Fusobacterium-killing antibiotic metronidazole, but not Correspondence to C.J.
erythromycin, inhibited patient-derived xenograft tumour growth. Christian.Jobin@medicine.ufl.edu

Finally, the authors investigated the
effect of metastasis-associated bacteria on
CRC metastatic growth by treating mice
bearing PDX tumours with antibiotics. The
Fusobacterium-killing antibiotic metroni­
dazole but not the antibiotic erythromycin
(to which Fusobacterium are resistant) sig­
nificantly inhibited growth of PDX derived
from an F. nucleatum culture-positive CRC
(P = 0.0005) and tumour cell proliferation
(P = 0.002). This observation, in line with a
previous report that F. nucleatum enhanced
HCT116 (a human colon carcinoma cell
line) xenograft tumour growth6, suggests that
targeting Fusobacterium could be a useful
strategy to treat CRC. Overall, the study by
Bullman et al.10 expands the field of micro­
biota and CRC research by demonstrating that
intratumour intestinal bacteria (specifically
Fusobacterium) could functionally influence
cancer metastatic colonization. Their findings
suggest that bacteria, at least in the CRC set­
ting, are an integral component of metasta­
sis, which has been primarily considered an
intrinsic property of transformed cells (FIG. 1).
From initiation to progression and treat­
ment, bacterial influence on CRC is broad,
and it is likely that specific microbial activi­
ties target each of these processes. The study
by Bullman et al.10 clearly showed the diverse
and complex effects intestinal bacteria exert
on the carcinogenesis process by aiding meta­
static growth. What is the clinical implication
of these findings?
Bullman et  al. 10 found that patients
with caecum or ascending CRC had worse
survival than those with non-caecum or
non-ascending CRC (P = 0.01). Interestingly,
Fusobacterium-positive primary and metasta­
ses tumour pairs were more likely to be
derived from caecum or ascending CRC, and
high Fusobacterium content (>1% relative
abundance) in primary caecum or ascending
CRC correlated with significantly poor overall
survival of patients (P = 0.004). These correla­
tions suggest that both location in the colon
and colonization levels are important for
Fusobacterium-mediated tumorigenesis and
that quantitatively screening Fusobacterium
in patients with caecum or ascending CRC
could be useful in predicting CRC outcomes.
In addition, bacteria present at other body
sites (skin, lung, stomach, pancreas) could
also participate in cancer metastasis, which
should be investigated.
This latest study raises a series of impor­
tant questions. Among them is the mech­
anism by which Fusobacterium promote
tumour implantation. Xenograft experiments
using Fusobacterium-negative primary CRC
pre-infected with Fusobacterium would estab­
lish the crucial role of Fusobacterium in meta­
static colonization. Identification of the host
gene repertoire associated with metastasis
and microbial genes responsible for tumour
implantation would help define a mech­
anism of action. CRC metastasis is a multi­
step process, and whether Fusobacterium
doi:10.1038/nrgastro.2017.186
Published online 17 Jan 2018
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metabolites, and colon cancer. Nat. Rev.
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inflammation, and colorectal cancer. Annu. Rev.
Microbiol. 70, 395–411 (2016).
3. Rubinstein, M. R. et al. Fusobacterium nucleatum
promotes colorectal carcinogenesis by modulating
E‑cadherin/beta-catenin signaling via its FadA
adhesin. Cell Host Microbe 14, 195–206 (2013).
4. Kostic, A. D. et al. Fusobacterium nucleatum
potentiates intestinal tumorigenesis and modulates
the tumor-immune microenvironment. Cell Host
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5. Gur, C. et al. Binding of the Fap2 protein of
Fusobacterium nucleatum to human inhibitory
receptor TIGIT protects tumors from immune cell
attack. Immunity 42, 344–355 (2015).
6. Yang, Y. et al. Fusobacterium nucleatum increases
proliferation of colorectal cancer cells and tumor
development in mice by activating toll-like receptor 4
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Acknowledgements
Y.Y. is supported by the Crohn’s & Colitis Foundation of
America (CCFA) research fellowship award (CCFA Ref.
#409472). C.J. is funded by NIH grants R01DK073338,
R01AT008623 and R21CA195226, and the University of
Florida Department of Medicine Gatorade Fund.
Competing interests statement
The authors declare no competing interests.

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