Sam Rhine - Genetic Update Conferences - www.samrhine.

com
Follow Sams Updates on Twitter: @samrhineguc
Genes and Cancer..!ncogenes and Tumor Suppressor Genes
Cancer Therap"..and Cancer Stem Cells
References: #. Chec$ out Sams %re&iews at: http:''samrhine.com'pre&iews'
(. !utloo$ Cancer Supplement) *ature) +ol. ,-.) pp. S,--S.-) /a" (.) (-#0
also in Scientific 1merican) Supplement) 2ul" (-#0) pp. S#- S3,
3. 4reast Cancer - Science 5Co&er 1rticle6) +ol. 303) pp. #0,#-#07,) /arch (8) (-#0
0. Cancer Stem Cells - Cell Stem Cell) +ol. #0) *o 3) pp.(7,-3(#) /arch 9) (-#0
,. Cancer :mmunotherap"..;4rea$through of the <ear)
Science) +ol. 30() pp. #03#-#003) =ecem>er (-) (-#3
9. ?e> Site: http:''www.>iooncolog".com'

@all Cancer is Genetic..>ut most Cancer is not :nheritedA
:. Genes and Cancer..
1. U.S. Buman Cancer Statistics for (-#0-#,:
-

CA: A Cancer Journal for Clinicians, Vol. 64, Is. 1, pp. 929, Jan/Feb 2014
4. 4asic Cancer Concepts:
#. /itosis and 1poptosis
a. /itosis - programmed cell >irth - one cell di&ides to >ecome two
prophase ' metaphase ' anaphase ' telophase
i. S"mmetric /itosis - for cell eCpansion - increase the num>er of cells
s"mmetric illustration
ii. 1s"mmetric /itosis - for cellular differentiation in the em>r"o
as"mmetric illustration
one cell is retained as the di&iding cell - ;Self Renewal
one cell go on a differentiation pathwa" - ;=ifferentiates
common t"pe of mitosis found in stem cells
iii. in the old da"s..Aall cancer was the result of too much mitosisA
>. 1poptosis - programmed cell death - eliminates unneeded) d"ing or
damaged cells - disco&er in the #.7-s

i. shrin$age ' >le>>ing ' fragmentation 5apoptotic >odies6 ' engulfment
ii. ;%rogrammed Cell =eath ' ;Cellular Suicide ' ;4le>>ing to !>li&ion
a neat) clean) tid"..no muss) no fuss..wa" to get rid of a cell
c. /itosis and 1poptosis -
i. cellular eDuili>rium..cellular homeostasis maintains the normal
num>er of cells in the >od"
ii. if the eDuili>rium is upset..inappropriate accumulation of cells
Too /uch /itosis - tumor../itosis out of control
*ot Enough 1poptosis - tumor..1poptosis out of control
d. Chemotherap" $ills cancer cells.. &ia 1poptosis
(. 1ll cancer 5all tumors6 originate from one single somatic cell

a. one single somatic cell is con&erted into a single cancer cell
>. the con&ersion is due to =*1 =amage in the original normal cell
c. that first single cancer cell is the ;Founder Cell - the Founder of the Tumor
d. the con&ersion of a normal cell into Founder Cell is ;Transformation
e. from the Founder Cell - the cancer) the entire tumor) will de&elop
f. Founder Cell F # cell out of 8-)---)---)---)--- - leads to the tumorG
3. Genome Sta>ilit" - we want the genome to >e Sta>le - *o Changes
Changes F the =*1 =amage that causes Transformation
a. GE*E /UT1T:!*S - a>out 0-- genes can mutate to cause cancer
i. !*C!GE*ES 5!*C6 - usuall" turned !FF
cause Cancer when mista$enl" turned !*
the gene mutation mista$enl" turns them !*
;1cti&ation /utation - 1cti&ates gene >" mista$e
acts as =ominant Genes - need onl" one of the two genes mutated
..H8-I of the 0-- cancer causing genes ' 3 letter nic$name
SRC SaRComa
R1S R1t Sarcoma
S:S S:mian Sarcoma
ER4 ER"thro4lastosis
/<C /<eloC"tosis
14J 14elson Jeu$emia &irus
4CJ( 4-Cell J"mphoma-(
ii. TU/!R SU%%RESS!R GE*ES 5TSG6 - usuall" turned !*
cause Cancer when the" are mista$enl" turned !FF
the gene mutation mista$enl" turns them !FF
;:nacti&ation /utation - :nacti&ates gene >" mista$e
acts as Recessi&e Genes - need >oth of the two genes mutated
..H(-I of the 0-- cancer causing mutations - nic$name
4RC1# 4Reast C1ncer K#
4RC1( 4Reast C1ncer K(
R4 Retino4lastoma
1%C 1denomatous %ol"posis Coli
=CC =eleted in Colon Cancer
%,3 %rotein ,3
iii. !*C!mirs - microR*1s from *on-Coding Genes - turn genes ;!*
i&. 1ll somatic cells accumulate cellular mutations o&er time
=ri&er /utations - dri&e the cancer - !*Cs and TSGs
cell growth ad&antage ' in&asi&eness ' metastasis
%assenger /utations - no cancer effect ' ;along for the ride
&. Cancer Causing /utations ma" >e ECogenous or Endogenous
ECogenous /utations - =ue to Factors !utside the 4od"
Carcinogen ECposure..Carcinogens F Cancer Causing 1gents
/ost Carcinogens are /utagens..the" cause mutationsG

En&ironmental or Jife St"le ECposures ECamples:
Cigarette Smo$e - o&er ,, Carcinogens L Jung Cancer
%1B - %ol"c"clic 1romatic B"drocar>ons
*icotine-=eri&ed *itrosoamines
%rimar" - Secondar" - Tertiar" Smo$e ECposure
Ultra +iolet Jight L S$in Cancer
:oniMing Radiation - N-ra"s O Gamma Ra"s
1s>estos L /esothelioma
+irus L Ji&er Cancer - Bepatitis 4
Cer&ical Cancer - Buman %apilloma +irus
4acteria L Stomach Cancer - Belico>ater p"lori
Jead L Jung Cancer
P !&er (-- ECogenous Carcinogens QnownGP
http:''www.cancer.org'cancer'cancercauses'othercarcinogens
'generalinformationa>outcarcinogens'
$nown-and-pro>a>le-human-carcinogens
&i. Endogenous /utations - =ue to Factors :nside the 4od" - inside a cell
=*1 replication errors at S %hase >efore mitosis

S-%hase Repair or /is/atch Repair:
=*1 Replication during S %hase - Replication enM"me is =*1 %ol"merase
=*1 %ol"merase alwa"s ma$es some mista$es: # ' #)---)--- nucleotides
Buman Genome contains L 3)---)---)--- nucleotides 5C( >oth sides6
9)--- replications errors ' per cell ' per mitosis
Replication Errors can result in /utations - Endogenous
:nterphase Repair:
=*1 mutations in s$in cells due to U+ eCposure - somatic cell mutation.
:nterphase Repair EnM"mes fiC the damage and correct the mutations
Bowe&er) if the Repair EnM"mes fail to correct the damage) or
if there are eCcessi&e mutations - too man" to repair..
Results in Endogenous /utations
>. CBR!/!S!/E 14*!R/1J:T:ES
i. Translocations - two chromosomes >rea$ and reRoin
eCchange parts of >etween two chromosome arms
often eDual eCchanges - reciprocal translocation
an oncogene can >e is acti&ated at the >rea$ point
leading cause of leu$emias and l"mphomas
ii. 1neuploid" - due to mitotic nondisRunction - add or lose chromosomes
eCtra chromosomes - eCtra copies of !*Cs
missing chromosome - lose copies of TSGs
ii. :nsertions or =eletions
:nsertions - can ramp up an !*C F turn it !*
1mplifications - ramp up an !*C
=eletions - can cause loss of a TSG F turn it !FF

c. CBR!/!TBR<%S:S - Chromosomes %ul&eriMed into Small Fragments
i. multiple chromosomes >rea$ and reRoin at multiple positions
ii. some chromosome fragments are lost in the process
iii. reRoining can lead to !*C 1cti&ation and ' or TSG :nacti&ation
i&. ma" >e an ata&istic mechanism - normal process in ciliated !C"tricia

d. E%:GE*ET:C CBR!/1T:* ERR!RS - !pens and ' or Closes Chromatin
i. B"per/eth"lation - Closes - genes !FF - can :nacti&ate a TSG
ii. B"po/eth"lation - !pens - genes !* - can 1cti&ate an !*C

0. 1ll Cancer is Genetic..>ut /ost Cancer is not :nherited
Remem>er: the terms Genetic and :nherited are not the same
a. :nherited - runs through the famil") passes from parent to child
passes through the egg and sperm from parent to child
often occurs in the famil" in consecuti&e generations
most cancer *!T inherited - Rust crops up...,I
.,I of cancer is S%!R1=:C
>. /ost cancer...,I: ?e inherit) from our parents perfectl" *!R/1J
=*1 in our genes and chromosomes
Then: some time during our life time..
i. *!R/1J GE*E /UT1TES - =R:+ER /UT1T:!*
an !*C or TSG L somatic cell mutation F ;F!U*=ER
ii. CBR!/!S!/E TR1*SJ!C1T:!* occurs) acti&ates
an !*C L somatic cell translocation F ;F!U*=ER
iii. CBR!/!TBR:%S:S occurs - acti&ates !*Cs or inacti&ates
TSGs L chromothriptic somatic cell F ;F!U*=ER
i&. E%:GE*ET:C CBR!/1T:* ERR!R occurs - !*C or TSG
leads to somatic cell with epigenetic error F ;F!U*=ER
/ost =*1 =amage that leads to cancer - occurs during our lifetimesG
c. 1>out ,I of Cancer..there is an inherited factor
:*BER:TE= %RE=:S%!S:T:!*
..increased chance..increased tendenc"
occurs with the TSGs..4RC1# ' R4 ' 1%C
i. inherit one 5of the two copies6 with a germ line mutation
mutation is passed through the egg or sperm
passing through the famil" F inherited
d. 4reast Cancer - women in US - # in 8 will de&elop >reast cancer F #(I
i. .,I - Sporadic 5usuall" late age of onset6
ii. ,I - :nherited %redisposition 5often earlier age of onset6
:f a ?!/1* inherits one 5of the two6 4RC1 genes with an
inacti&ating TSG dri&er mutation..
4reast Cancer ris$ goes from #(I to 8-I and..
!&arian Cancer ris$ goes to ,-I
:f a /1* inherits one 5of the two6 4RC1 genes with an
inacti&ating TSG dri&er mutation..
increased chance for pancreatic) prostate and male >reast Ca
,. Bow do /ost Tumors =e&elopS
a. Founder Cell gi&es rise to the %rimar" Tumor - 8 to #- "ears
Few cancer deaths are caused >" the primar" tumor.
/ost cancer deaths due to /etastasis..Spreading thru >od"
>. /etastasis - migration of cancer cells from the %rimar" Tumor into
other remote >od" tissues..where the" can ;seed and esta>lish
Secondar" TumorsG /ost cancer deaths from secondar" tumorsG
c. ECample: %rimar" Tumor de&elops in the >reast where it is localiMed
at the site where it originated. 4ut as the tumor continues to
de&elop it accumulates new mutations and >ecomes ;:n&asi&e..
in&ading areas of the tissue >e"ond the limits of the original tumor.
The in&asi&e cells ma" gain entr" into a >lood &essel and then
tra&el all through the >od" &ia the circulator" s"stem..
or it ma" gain entr" into l"mphatic &essel and then tra&el all
through
the >od" &ia the l"mphatic s"stem.
The cancer cells can then eCit from the >lood &essel or l"mphatic
+essel and some distant tight and ;seed secondar" tumors in the
>one) lung) li&er) colon etc.
/ost cancer deaths from secondar" tumorsG


d. Epithelium and E/T
i. Epithelial Cells form a co&ering or act as a lining in the >od"
ii. sits upon a >asement mem>rane - laminar matriC
iii. >elow the >asement mem>rane is the connecti&e tissue with:
>lood &essels) l"mphatic &essels and ner&es
i&. epithelial cells with cell to cell adhesion and rigidit" F little >oC
4UT..epithelial cells can lose their rigidit" and con&ert into
migrator" cells T /esench"mal Stem Cells - which can mo&e
throughout the >od" - E/T: Epithelial to /esench"mal Transition
Cells con&ert to a cell that can >e :n&asi&e and /etastasiMe
e. Step >" Step of Tumor Formation
i. !ne epithelial cell acDuires a mutation - !*C or TSG
that single cell 5orange cell6 is the ;Founder Cell
it can grow faster than the other normal cells
Jeads to a ;Clone of the Founder Cell F ;Clonal ECpansion
Jets chec$ >ac$ at the same site..four "ears later.
ii. Four "ears since the origin..
See an accumulation of orange clone F ;B"perplasia
!ne orange cell acDuires a second mutation 5pin$6
%in$ cells can grow faster than the orange cells
Second clonal eCpansion of pin$ cells F Two clones in the tumor
Jets chec$ >ac$ at the same site..four "ears later.
iii. Eight "ears since the origin..
See an accumulation of pin$ and orange clones F ="splasia
!ne of the pin$ cells acDuires a third mutation 5la&ender6
Ja&ender cells grow faster than the pin$ cells
Third clonal eCpansion of la&ender cells F Three clones in tumor
Jets chec$ >ac$ at the same site..four "ears later.
i&. Twel&e "ears since the origin..
%rimar" tumor - still localiMed - cancer in situ..three clones
!ne of the la&ender cells acDuires a fourth mutation 5>lue6
4lue cells go through the E/T con&ersion - >ecomes in&asi&e
penetrates through the >asement mem>rane and in&ades the
underl"ing connecti&e tissue - ;:n&asi&e Tumor - four clonesG
Jets chec$ >ac$ at the same site..four "ears later.
&. #9 "ears since the origin..
!ne of the >lue cells acDuires a fifth mutation which
%ermits the cell to >rea$ awa" from the tumor mass and enter
a >lood &essel - >eginning of /etastasis - fi&e clones
Jets chec$ >ac$ at the same site..four "ears later.
&i. (- "ears since the origin..
, mutations - , clonal eCpansions
:n&asi&e) /etastasiMing) Jife Threatening Carcinoma
Carcinoma is a tumor that originates from an epithelial cell
Tremendous Tumor Beterogeneit"
9. Tumor Beterogeneit" - CompleCit" of a Tumor
a. 1ll the com>inations of o&er 0-- mutated !*Cs and TSGs
=ri&ers and %assengers
>. %lus chromosomes: Translocations ' 1neuploidies ' :n=els
c. %lus Chromothripsis
d. %lus Epigenetic Chromatin Errors
e. CompleCit" of =iagnosis and Therap"
/iCture of ECpanded Clones
some with /ET and others with E/T cell re&ersion
/iCture of Therapeutic Targets
f. TCG1 - The Cancer Genome 1tlas
Jung 1denocarcinoma - leading cause of cancer death
in the world..L#)---)--- per "ear
Cancer Cell /utations: =ri&ers U %assengers F 8.. ' #)---)---
*ormal Cell /utations: %assengers F # ' 3-)---)---
Cancer Cells: (9, fold increaseG
#8 =ifferent =ri&ers - Significantl" /utated
EGFR in females ' R4/#- in
males
*ew S"stem for Cancer Classification:
/olecular &s. Bistopathologic 5microscopic6
*ature) &ol. ,##) pp.,03-,08) 2ul" 3#) (-#0
/ultiplatform 1nal"sis of #( Cancer T"pes Re&eals /olecular
Classification within and across Tissues of !rigin
Cancers are more li$el" to >e geneticall" similar >ased upon
their cell t"pe of origin rather than their organ of origin
1>out #-I of cancers toda") would >e improperl" classified
with the new s"stem..diagnosis..therap"..prognosis
g. ECample of Tumor Formation - Colorectal Cancer


7. Bow do !ncogenes and Tumor Suppressor Genes Cause
CancerS
a. ?hat is a tumor - inappropriate accumulation of cellsG
?hat causes - inappropriate accumulation of cellsS
- inappropriate mitosis - mitosis at the wrong time
>. Cell C"cle - Jife C"cle of a Cell

i. G# - Gap in time >etween the last mitosis >efore S
S - S"nthesis of =*1 - go from 09to .( chromosomes
G( - Gap in time >etween S and /itosis
/ - /itosis: %rophase ' /etaphase ' 1naphase ' Telophase
ii. C"cle is usuall" turned off - onl" turns on for mitosis

iii. ?hat $eeps the c"cle turned offS %rotein %adloc$
i&. Two 4ig Vuestions: ?hat turns the c"cle !*S
?hat unloc$s the %adloc$S
?hat turns the c"cle !FFS
?hat is the %rotein %adloc$S
c. ?hat turns the c"cle !*S ?hat unloc$s the %adloc$S
#. SET of *!R/1J GE*ES..which produce a
(. SET of *!R/1J ;:*1CT:+E %R!TE:*S
3. SET of %R!TE:*S when ;1CT:+1TE=
produce a CEJJ S:G*1J %1TB?1<
0. CEJJ S:G*1J %1TB?1< - TUR*S C<CJE ;!*



d. Cell C"cle 2argon..
CEJJ S:G*1J %1TB?1<
%R!TE:* 1CT:+1T:!* REJ1<
CEJJ S:G*1J TR1*S=UCT:!* S<STE/
SEC!*= /ESSE*GER S<STE/
e. *ormal Genes) H0--) can mutate to cause cancer
i. !ncogenes - !*C:
=ominant Trait - !ne 1llele /utates
ii. Tumor Suppressor Genes T TSG
Recessi&e Trait - 4oth 1lleles /utated
TSG mutation F B:T
f. TSG - Tumor Suppressor Genes..
:*BER:TE= %RE=:S%!S:T:!*
i. Retino>lastoma 5R46 - cancer of the retina of the e"e
R4 Gene at #3D#0.( - produces the R4 %rotein

g. ?hat does the R4 %rotein doS
Cell C"cle Repressor..R4 %rotein is the %1=J!CQ

h. !*C F !*C!GE*ES - summar"

There are normal genes that produce normal ;inacti&e
proteins) which are part of the Cell Signal %athwa"
Under normal conditions those proteins are ;acti&ated onl"
during normal mitosis at / of the cell c"cle
4UT: :f those normal genes mutate) the mutation can cause
the production of a>normal ;acti&ated protein which
can cause the pathwa" to send a mitosis signal at the
wrong time F inappropriate mitosis F cancer
i. TSG F TU/!R SU%%RESS!R GE*ES - summar"
*ormall" the cell c"cle is !FF) and it is loc$ed !FF >"
certain normal genes that produce normal proteins that
act as a cell c"cle padloc$
4UT if the those genes mutate) and the proteins are no
longer
produced) then the %1=J!CQ is missing and the c"cle is
no longer loc$ed ;!FF which lea&es the c"cle ;!*.



8. Cancer Stem Cells
a. ;STE/*ESS - the uniDue characteristics of stem cells
i. Self Renewal - with as"mmetric mitosis mechanism
cell proliferation
ii. =ifferentiation - with as"mmetric mitosis mechanism
produce an" of ((- human cell t"pes
iii. /igration - E/T transition
migrate throughout the >od"
i&. %rotection from =*1 =amage
pump ' purge harmful chemicals and repair ;lethal damage
>. ?hat if the Founder Cell..is a Stem CellS
C1*CER STE/ CEJJ - Founder Cell with ;Stemness
i. Self Renewal - Tumor Cell %roliferation
=ri&es Tumor Growth
ii. =ifferentiation - %roduce all the tumor cell clones
=ri&es Tumor Clone =e&elopment
iii. /igration - /igrate throughout the >od"
=ri&es Tumor /etastasis
i&) %rotection from =*1 =amage - Resist chemo O radiation
=ri&es Tumor Recurrence
c. /an" Cancer Therapies..Chemotherap" and Radiation..
i. =estro" the >ul$ of the tumor cell clones..so the tumor shrin$s
and sometimes disappears
ii. 4ut ma" ultimatel" fails >ecause the" do not $ill that small
population of Cancer Stem Cells - leading to recurrenceG
iii. Future: Com>inational Therap"
Chemotherap" or Radiation to destro" the >ul$ of the tumor
cell clones..
Com>ined with separate drugs that will selecti&el" destro"
the Cancer Stem Cells
i&. ECamples:
G4/ - Glio4lastoma /ultiforme >rain tumor - primar" tumor
resistant to Radiation Therap"
1/J - 1cute /"eloid Jeu$emia
most common acute leu$emia in adults
d. C=-07 - 5Cluster of =ifferentiation 076
i. C=-07 is a molecule found on the surface of man" human cells
ii. it instructs circulating macrophages not to destro" those cells
C=-07 is the @=ont Eat /eA signal
iii. the >od" uses C=-07 protein on the cell surface to protect cells
from >eing destro"ed when the cells are "oung
>ut diminishes when the cells get older and need to >e replaced
new R4Cs ha&e lots of C=-07 when first produced
>ut C=-07 is lost as the" get older L macrophage destruction
i&. B!?E+ER..
most cancer cells ha&e large amounts of C=-07 on surface
the C=-07 protects the cancer cells from >eing destro"ed >"
the macrophages of the immune s"stem..
the ;=ont Eat /e signal protects the cancer cells from
natural) normal) immune destruction
e. 1nti C=-07 Therap" for 1/J 51cute /"eloid Jeu$emia6 in mice
i. the 1/J Jeu$emia Stem Cell 5JSC6 is co&ered with C=-07
ii. %rotecting the JSC from macrophage immune destruction
iii. /onoclonal 1nti>od" against C=-07 549-B#(6
..mas$ed the C=-07 on cancer cells - 1/J disappeared
i&. C=-07 is found in large amounts on the surface of nearl" e&er"
t"pe of Buman Cancer Stem Cell.
&. Buman C=-07 human trials >egan on 1ugust #,) (-#0 for
human o&arian) >reast) colorectal) pancreatic and >rain Ca
Stanford Uni&ersit" trials: http:''stemcell.stanford.edu'C=07'
f. Buman Em>r"olog"
i. ((- specialiMed human somatic cells de&elop from the M"gote
>" wa" of ((- one wa" streets ' ((- sets of signals
to form ((- terminall" differentiated somatic cells
i.. as =:FFERE*T:1T:!* %R!GRESSES..
SEJFRE*E?1J REGRESSES
Trade off: Gain SpecialiMation >ut lose /itotic a>ilit"
((- terminall" differentiated cells cannot di&ide
Cannot >ecome a F!U*=ERG
?here do "ou find mitosis in the human >od" cellsS Stem CellsG
1ll F!U*=ERS..all C1*CER..come from STE/ CEJJS
g. Future %ossi>ilit"..
Screening for new cancer stem cells with C=-70
4egin C=-07 anti>od" therap" &er" earl" - $noc$ out the CSCsG
ST!% C1*CER 4EF!RE :T 4EG:*SGG
.. Cancer Therap" - the ;=RE1/../agic 4ulletG
/agic 4ullet Therap": attac$s onl" the cancer cells and
does not harm an" normal somatic cells
a. Tumor remo&al >efore metastasis:
pol"p lasso ' s$in cancer resection ' surger"
>. !rgan remo&al >efore an" cancer occurs: mastectom" and or
oophorectom" with a 4RC1# mutation carrier
>. Chemotherap": harsh c"totoCic chemicals that can cause the
death of rapidl" di&iding cancer calls &ia apoptosis
c. Radiation: direct radiation at rapidl" growing cancer cells
leading to chromosome damage and cell death
d. 4one /arrow Transplant: destro" the ?4C with leu$emia
replace them with new normal ?4C - self or donor
e. Targeted Therapies: Glee&ec - focus to correct the 4CR'14J
oncoprotein in Chronic /"eloc"tic Jeu$emia
f. :mmunotherap" - induce the immune s"stem) T-Cells) to
attac$ and destro" the tumor
g. Bormonal Therap" - some >reast and prostate tumors can >e
affected >" adding or remo&ing certain hormones
li$e estrogen or testosterone
h. 1ngiogenesis :nhi>itors - all tumors need their own >lood
suppl" to sur&i&e) these therapies stop the formation
of
new >lood &essels in a de&eloping tumorW
i. 1nti>od" 4loc$ing: >loc$ signal pathwa" receptor - Berceptin
>loc$s the BER'new receptor so the oncoprotein
signal cannot initiate the a>normal mitosis signal
R. micro R*1: man-made microR*1 molecule can selecti&el"
turn of one specific oncogene - prostate cancer
$. +accines - for cancer caused >" !nco&iruses li$e Bepatisis
for li&er cancer and B%+ for cer&ical cancer
$. Therapeutic Cancer +accines - use cancer cell proteins to
stimulate the immune s"stem to attac$ the cancer
l. JiDuid 4iops" - nearl" e&er" tumor sheds =*1 into the >lood
new tests are coming to diagnosis an" cancer from a
simple) annual) >lood e&aluation.
m. Epigenetic Therap" - =emeth"lation of Chromatin for !*C
..%lease get Cancer Screening ECamsGG
#-. Cancer 2argon
*eoplasia - ;*ew Formation) &er" general term) a rapidl" growing a>normal tissue
*eoplasia L *eoplasm L Tumor
Tumor - a>normal mass of cells) growing more rapidl" than normal..
inappropriate accumulation of cells
Founder Cell - the original) single) mutated cell that will transform and de&elop into
the tumor
Transformation - the con&ersion of a normal somatic cell into a mutated cancer cell
with malignant potential due to some t"pe of =*1 damage
Clone - group of geneticall" identical cancer cells deri&ed from one mutated cell

Clonal ECpansion - the de&elopment of a mass of mutated cells in a tumor clone
%rimar" Tumor - localiMed and >enign) cancer in situ) often the first stage where
the de&eloping tumor is recogniMa>le.
/etastasis - spreading of cancer cells from the primar" tumor to other remote areas
of the >od" through the >lood stream or l"mphatic s"stem where the cells
can ;Seed the formation of secondar" tumors.
Secondar" Tumor - tumors that de&elop at &arious sites around the >od" after >eing
distri>uted and ;Seeded >" metastasiMing cells form a primar" tumor.
4enign - a tumor which is localiMed at the site where it originated) it has not spread
has not metastasiMed..Safe
/alignant - tumor characteriMed >" uncontrolla>le growth) in&asi&eness and
/etastasis - @Jife ThreateningAG
Cancer - +arious t"pes of malignant neoplasms) most of which are in&asi&e and
/etastasiMe
Solid Tumor - cancer cells pac$ed and growing together in a unified mass
=ispersed Tumor - cancer cells proliferating indi&iduall" - not pac$ed together
Jeu$emias and J"mphomas
1cute - cancer with a relati&e short time course) sometimes onl" months from
diagnosis to death
Chronic - cancer with a relati&el" long time course) ma" >e man" "ears from
diagnosis to death
!ncolog" - the stud" of the causation) pathogenesis and treatment of cancer
Carcinoma - cancer where the Founder Cell was an epithelial cell
Sarcoma - cancer where the Founder Cell was a connecti&e tissue cell
Jeu$emia - cancer where the Founder Cell was a Jeu$oc"te F white >lood cell
J"mphoma - cancer where the Founder Cell was a J"mphoc"te F white >lood cell
/elanoma - cancer where the Founder Cell was a melanoc"te F pigmented s$in cell
::. Regenerati&e /edicine..Tissue Engineering
%roducing Replacement Buman Tissues
and !rgans in the Ja>orator".X*eo-!rgansX
1. U.S. !rgan Transplant Statistics for (-#0-#,:

#. ?h"S L#(()--- persons in US - waiting for an organ transplantG
a. Y 3-)--- will recei&e a transplant - L .()--- die while waiting
heart) lung) li&er) $idne") pancreas etc. - too few donorsG
>. a&erage person on li&er waiting list..waits (9 monthsG
c. a&erage person on lung waiting list..waits 3 "earsG
H,-I of those o&er ,-) waiting for $idne") will die while waitingG
(. Regenerati&e /edicine:
inducing human tissues that are damaged) worn out or missing..
to regenerate and return to their normal state
persuading the >od" to heal itself through the deli&er") to the
appropriate site) of cells) >iomolecules and ' or supporting
structures
3. Tissue Engineering: production of human tissues and ' or organs in
the la>orator") and their su>seDuent transfer >ac$ into the >od") to
compensate for an organ ' tissue that is missing or not functioning
normall"
4. 4asic !rgan Transplant Concepts:
#. Tissue and !rgan Sourcing..
Sources of cells for transplantation and regenerati&e medicine:
a. Bistocompata>ilit" and ReRection: BJ1 S"stem
Buman Jeu$oc"te 5?4C6 1ntigens
>. ?hat causes reRectionS :mmune S"stem: =iscriminates >etween
XSelfX and X*on-SelfX - protects self ' destro"s non-self
:mmune attac$ orchestrated >" the T l"mphoc"tes F ?4C
attac$ and destro" *on Self 5foreign6 tissues
i. 1utograft 51utologous6
1uto F self - use "our own tissue - no reRection
ii. :sograft 5:sologous6
:so F eDual - use tissue of identical twin - no reRection
First Qidne" Transplant - =ecem>er (3) #.,0
=r. 2oseph /urra" - Bar&ard /edical School
*o>el %riMe in /edicine - #..-
Berric$ Twins - Ronald ' =onor O Richard ' Recipient
iii. 1llograft 51llogenic6
1llo F =ifferent - use tissue from a different person
L ReRection - usuall" need immunosuppressi&e drugs
i&. Nenograft 5Nenologous6
Neno F foreign - use tissue from a different species
pig &al&e into a human heart
&. 4iocompati>le material - inert F not reRected
plastic) titanium) aluminum) ceramic
c. Bost &. Graft - most medical reRections
Bost 5%atient6 reRects the Transplant 5Graft6
d. Graft &. Bost - some medical reRections
Transplant 5Graft6 reRects the Bost 5%atient6
G+B= - Graft +ersus Bost =isease
4one /arrow 54/6 transplants ' Face transplants
Jarge num>er of ?4C in 4one /arrow ' Face
(. =onor Cell or Tissue Sources:
a. 1dult Somatic Cells and Tissues
>. Em>r"onic Stem Cell deri&ati&es
c. 1dult Stem Cell deri&ati&es
d.. i%S - induced %luripotent Stem deri&ati&es
Stem Cells made from s$in - no em>r"os used
3. SC1FF!J= - Framewor$ for the engineered tissue or organ
S"nthetic: 4iocompati>le ' 4iodegrada>le /aterials
%ol"mers: %G1: %ol"Gl"colic 1cid
Ceramics
*atural: Collagen
C. Tissue Engineering ECamples:
a. BSE - Buman S$in EDui&alent
i. Scaffold F >o&ine t"pe : collagen
U Epidermis F $eratinoc"tes U =ermis F fi>ro>lasts
ii. %rimar" Use - s$in grafts in >urn &ictims
>ed sores ' dia>etic s$in ulcers
E4 - Epidermol"sis 4allosa /:/ F K((97---
Geneticall" Engineered S$in - Tissue Engineering U
Genetic Engineering
S$in Cell =onors - new>orn >a>" 4!<S..
one donation L co&er 9 foot>all fields
iii. S$in Cell Gun - Spra"-on S$in http:''en.wi$ipedia.org'wi$i'S$inZcellZgun

>. Urinar" 4ladder - often too small - due to neural tu>e defect
i. Urinar" 4ladder - inner Uroepithelium ' outer Smooth /uscle
ii. 4iops" eCisting >ladder cells for new >ladder F autologous
Separate >iopsied Epithelial cells from /uscle Cells
ECpand 5increase num>er 6 >oth cell t"pes in &itro &ia mitosis
Transfer to 4iocompati>le 4iodegrada>le Scaffold - %G1
From >iops" to surgical insertion F 7 - 8 wee$sG 4ladder Ca
c. *ose - 4ec$ ?eathers - from se&ere frost >ite
%G1 scaffold - loo$s li$e st"rofoam
seeded inside and out with patientXs own cells F autologous
d. Ear - Treacher-Collins S"ndrome
Scaffold: 4iocompati>le 4UT *!T 4iodegrada>le
:nitiall" Grown in petri dish..then transferred to under the
s$in of a mouse for completion
e. Chin ' 2aw - facial cancer
titanium mesh cage scaffold U >one mineral >loc$s U 4/ miC
U recom>inant 4/%-7 - grown initiall" in latissimus dorsi
f. Finger - porous ceramic scaffold
seeded with patients cells F autologous
g. 1rteries ' +eins - flat sheet and then rolled into a tu>e - li$e pasta
h. Corneal Epithelium - grow new cornea epithelium cell la"er within a
plastic >oundar" ring T ta$es H(# da"s
>iops" cornea epithelium lim>us stem cells from peripher" of the
e"e T ;seeded into the plastic ring
or >iops" oral epithelium to ma$e new cornea
transfer with no suture - 3, minutes with local anesthesia
i. Teeth - grow an organ in a test tu>e
R. Encapsulated Cell Therap" for T"pe # =ia>etes


First Buman Trials - implant capsules under the s$inG
http:''www.sciencedail".com'releases'(-#0'-.'#0-.#--.3-,(.htm
Encapsulated Cell Therap" - capsule the siMe of a pencil lead
Retinitis %igmentosa ' Buntington =isease ' %ar$inson =isease
capsule contains cells producing therapeutic protein
therapeutic protein eCits through pores in the capsule)
4UT immune cells 5?4Cs6 cannot enter to initiate reRection
$. Jigaments ' Tendons - !r> ?ea&er spider we> protein
strongest >iological molecule
produced >" transgenic goats or E. coli
l. Sutures - co&ered with autologous cells ' can >e geneticall" engineered
%etroleum 2ell" - X+aselineX Gene Therap" - for eCternal use on s$in
m. Qidne" - First /an-/ade - X!rganoidX - (--0 - from >o&ine ESCs
1rtificial human $idne" lined with human renal cells
n. Ji&er - Ji&er Cell 2et %rinter
inRect liDuid pol"mer into li&er &asculature
digest awa" all the li&er cells
lea&ing 3-= pattern of normal li&er &asculature
&asculature pattern is programmed into computer
program ma$es la"ers of scaffold with holes for >lood &essels
X%rinterX distri>utes li&er cells across the scaffold la"ers
la"ers are then tiered >ac$ together L Ji&er in &itro
o. Beart - /echanical heart to $eep heart transplant patient ali&e until
a donor heart >ecomes a&aila>le
Beart - *atural ' normal heart scaffold eCists within e&er" heart
=ecelluariMation - =etergent %erfusion
<ields normal heart Scaffold
RecellulariMation
p. Rat Jung - =ecellulariMe ' RecelluariMed lung cells from murine ESCs
D. /ouse Ji&er - =ecellulariMation and RecellulariMation
r. Buman Qidne" - human cells recelluariMe a pig $idne" scaffold
success in the rat - 1pril (-#3
s. Rat Qidne" success T decelluariMe ' recelluariMe - /a" (-#3
t. Trachea - damage from tu>erculosis - stripped and reseeded with
/SCs from 4one /arrow
u. Beart +al&e - anomal" diagnosed in un>orn >a>"
amniocentesis to o>tain /SCs used to construct
new heart &al&e >efore >irth - surgical replace old &al&e
&. !steogenesis :mperfecta 5!:6 - &er" fragile >ones prone to multiple
fractures - diagnosed in utero &ia amniocentesis
mothers /SCs inRected into the um>ilical cord >efore >irth
&ia chordocentesis - !: corrected
w. Finger Regeneration - use powder from dessicated >ladder of a pig
grew >ac$ in 0 wee$s
http://www.cbsnews.com/video/watch/?id=3805459n
C. /aSC - 1dult /ammar" Stem Cell
regenerate murine mammar" gland from one stem cell
%SC - %rostate Stem Cell
regenerate murine adult prostate from one stem cell
". /ouse ' Rat Em>r"o Chimeras - 4lastoc"st Complementation Test
in &i&o !rganogenesis
%roduce an organ of one species from the de&eloping em>r"o of
another species
%roduce a rat pancreas in a de&eloping em>r"o of a mouse
%lace rat 5>lue6 i%SCs in the >lastoc"st of a geneticall" modified)
pancreatic deficient) mouse em>r"o - and the mouse em>r"o
produces a rat pancreas
This can >e made to wor$ >etween an" two mammals..
and human are mammals
Future therap" for human T"pe : dia>etes..S
4egin with human =ia>etic i%S F =i%S) %lace human =i%Ss in the
>lastoc"st of a geneticall" modified) pancreatic deficient
pig em>r"o - the pig em>r"o would ma$es a human pancreas
transplanta>le into the human =i%S donor
Updated - Septem>er (9) (-#0