~

UNIT 4: CELL COMMUNICATION/CELL SIGNALING& IMMUNOLOGY

_ _ _ _ _ _ _ _ ___:____=-::--=--=-=--=-==-:....=~=-=~-=-=---=-=-=----'e
~1':~i~is vita~~•: the maint_rnnnrf_a_!1d s1;~·i"..'1l_of tiss_!J~S. De~ive laminins ra_ri c:at!S~~rnsr\r~_!Q.Jorm in12ropcfly leading to form
...... ular ,strophy 1£!_hal ~k).!l bhstenng disease Uunct1onaTep.wcrmolysis bullosa) and defects o the kidney filfur *' -
-----
{nepnrotrc syndronw).

Matri"\: Degradation
----=---· - -- -------- - - - -- -

Matrix romponents are degraded by extracellular proteolytic enzymes. Most of these are matrix metalloproteases, which depend on
b ~i• or Zn 2 • for activity, while others are serine proteases, which have a reactive serine in their active site.

The ~cgradation of matrix components is subject to complex controls, and cells can, for example, cause a localized degradation of
matnx components to clear a path through the matrix.

E.'\.-tra
-::,,.;:-
!\ form of the basem_ent memb~ane is commercially available. It is deri\'ed from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma, a tumor that C
1s. nchrn ECM ~rotems. Its maJor components are laminin, collagen 11V, heparan sulfate proteoghTan, and'
mdogen/entactm.
Vitamin Ci~ r~q_uired the acthity of prolyl-4-hydroxylase and lysyl-hydroxylase.
C?steogcnes1s 1mperfecta - Caused by a mutation in type 1 collagen dominant autosomal disorder results in weak bones and irregular connecthc
C
tissue, some cases can be mild while others can be lethal. ' '
Chondrodysplasias - Skeletal disorder believed to be caused by a mutation in type 2 collagen.

D.CANCER
Cancer is a class of disea~es in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissu~s,
and sometimes metastasis, or spreading to other locations in the body via lvmph or bloo.d., ~ C

'
All Cancers divided into two groups:

Those with an e~vironment~ ca~se and those with a hereditary genetic ca1!se.
C_
Cancer is primarily an environmental disease, though genelics influence the risk of some cancers.
Common environmental factors leadmg to cancer include: tobacco, diet and obesity, infections, radiation and environmental
pollutants. These environmental factors cause or enhance abnormalities m the genetic material of cells.
C:
Cell division is an extremely complex process that is tightly regulated by several classes of genes, including oncogenes and tumor suppressor
genes. Hereditarv or acquired abnormali'ie~ in these regulatory genes can lead to the development of cancer. A small percentage of cancers,
approximate I) 5 to 10 percent, are entirely hereditary j rl'l•,l k
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Properties of Cancer Cell
- -=-~ ~~~• /j r: v
• 1r beh vmr of ca11ccr ce:ls 1~ most ras ly stt,died 1~ vitro conditions.
Car~ r Is can be obt:iinect fr.2,!!!_ n alignant tumor ~d.se~rate cell~, ~nd C_!llturing t~e cells in vitro. Altemativth, normal cells can be
cJnv rtc.d o canctr cell~l:-y trrntmrnt with camnogrn1r chem1cals, rad1at10n, or tumor VJ ruses.

c s tha 'lave been• , nsformed m vitro by cm1caL or viruses can generally cause tumors when mtroduce<l into ,1 host amn

I vel tht mo~ important ch racte istic of a cancer cell-is itJ loss of growth control
r r eel ~, re groHn 1 1t1s ... ue 1.Jltu c under conditions that pr?mote cell prolif~rahon, they gro,, ,md div1d~ ta rate s1m,l,u t >t 1, •
11
, eu hgnu t coJ ite parts. However, when the norma_l cells p_rohferate to the pomt where they cover the bottom of the cu tur dash
r , t r; e derreas ~ marked y, nd they tend to remam as a smgle layer (monolaycr) of cell~

v. mahgnant cells 2 rr ct.ltured under the sam~ conditions, they continue to grow, p1hn° on top of onr ,mother• form "
1 11

>w t ar rliVJ 10n

nan• cr ls re not responsive to the types of signals that cause their normal co,mterparts I
10
ls th • r
r cells ignore inhibitory growth signals. they continue to grow in the absence of t1mu·

re depePct supplementation of growth factors, such as ep1dem1 I growth fact.Jr

of'> >oC'), which is usually added to the growth medmm

p I t .it m the absence of scrum because their cell cyde does not dept:, d on tht i 1tc
- v. be ar located t the cell surface

culture exhibit a limited capacit) for cell division after ir.ite un:. rr o m
n rs them unfit t cont nue to grow and divide

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nr , 111111~1~ Immortal l11, 111 c 1l11 y, 0111111111 to d1v1d1 111cld1111h ly

oflrn 11tnh111l'd to tl11 p11 1·1wc of h•lomcra'ic in I anc Ir q•ll ,111d 11

from mo t type of nonn,1I n-11:i r thou~ht to be one of tlwbody' nrnJor dcfcn cs that pro c1 n t t mor

km alterationN in the nucleuN following transformation occur within the chromosomes. Normal cell maintain their
cnrorno:sor I I, mph ntl'nt I th, y grow and divide•, both in vivo and 111 vitro.·
11
r II nrc genetically unstable and often have highly aberrant chromosome complements, a condition termed
\\luch ma, occur prrmanly as a result of defects in the mitotic checkpoint or the presence of an abnormal number of
h.t. oCCV'\cvv.C• o!, 1(ct)""'°'<~ e.:sAvo... I(,() MIM'"'9 e.-l.n\'.0t"'OS~ ie_od,"".1 ~ ~ X
anew cells 1s much less dependent on a standard diploid chromosome content than the growth of normal cells.

th chromosome content of a normal cell become.cl disturbed, a signaling pathway is usually activated that leads to the apoptosis
stru tton) of the cell. In contrast, cancer cells typically fail to elicit the apoptotic response even when their chromosome content
be1:on1~ 1 hi) deranged.

fr m apoptosis is another important hallmark that distinguishes many cancer cells from normal cells.

n be noted that cance+-~.ofren. depend on anaerobic fermentation (glycolysis), which is an a!!.aerobic metabolic pathway.
nr11 n ... rtv may reflect the high metabolic requirements of cancer cells and an madequate blood supply within the tumor.

nd1t1ons of hypoxia (reduced 02), cancer cells ac.1ivate a transcription factor called HIF that induces the formation of new blood
n promotes the migratory prope11ies of the cells, which may contribute to the spread of the tumor.

duct of glycolysis 1s lactic acid, which is secreted into the tumor's microenvironment, where it may promote tumor gro-wth.

C nee ypes

1fied by th type of cell that the tumor resembles and is therefore presumed to be the origin of the tumor. These types

1v d from epithelial cells Thi group includes many of the most common cancers,_ including those of the breast,

v d f om ~onnective tissue, or mesenchymal cells.

---,--.mia ( ancer derived frc m hematopoietic (blood-forming) cells

m immatun 'precursor" or embryonic tissue. These are also commonest in childre.n.

t nvironmental disease with 90-95% of cases attributed to environmental factors and 5-10% due to

u-,mnnr,n , n,.rmmrnr11tal fac 01 tl t wntnbute to cancer death include: tobacco (25-30%), diet and obesity (30-35%), mfect10ns (15 20%)
0

nd non onizing, up to 10%), stress, lack of physical acfivity, and environmental pollutan\s.

bl hack to DNA mutations that impact cell growth and metastasis. The mutagens h t ca

to p cific types of cancer Tobacco smoking 1s associat d with man fo d au

'----.-· ---:-;---::n -..=.::u....,,,.,~ s may P.romote cancer throug_h stimulatm~ the rate of cell
r to repair damaged DNA dunng DNA re mcreasmg th

_!IDC!.,"!_D__~arc:1_m>gens, m I mg nitrosamines nd polycyclic aromatic hydrocarbons

 l )I\IMl NICA1 ION/CJ IL SIGNALING& IMMU
ht 1s ,1 , net 11,•cl w11h 1h1• cl1•vl'lo1111u•11t of man y typ1•s of c;incer and 1~ a fo1to1 JJl 14 ',1./J% of all can 'r
, , 1111!11hut1 tn l'a1111 1 nsk not onl y th1,n1gh its dfl•ct rm body wf'ight bu t also through rwgat,vc cffr c:u
1' 111

,, 111 ,, , t 1blt, h 1111 ~ .1111l "holt g11ins, ,111d hi~h 111 proC'essc·d cJJ reel meats are linked with a number of cancers, C
'-lllt dll't I, llnkt•d to gnstrk 1·1111(·t•r, ,1!l,1toxm 111 , a f1 eq1H'nt food contaminate. with liver cancer, and Betel nut chewing with oral
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lnfoct10n

1pprox1matd 18 of eamcrs are rdated to mfectious diseases.

, r u,u infecllous ,1gcnts that cause cancc1 but bacteria and parasites may also have an effect.
\ I
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\ , n 'th. t .m ,1use (',lllCl' J 1s callccl_an oncovirus. These include hu111an~pillomaVJrus (cervical carcinoma), Epstein-B~rr.Yinis (B-~ell
\'tllpl proTif,•rulJ\C d1s,•asP and nasopharyngeal carcinoma), Kaposi's" sarcoma herpes virus (Kaposi's Sarcoma and pnmary effusion
h om ) hl'patitis JI and hepatit is C..':'.iruscs (hepatocell ularcarcmomaT, and Human 'r-celTTeukemia virus-1 (T-cell leukemias).

n I nfl' lion m.1y also increase• the 11sk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma

t mf ction ~trongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) _and the
k Op1 thorch1s viverrini and Clonorchis sincnsis (cholangiocarcinoma).

Radi hon

11c arc related lo rad1~tion cxposure either ionizing or nomonizmg.

....
1112mg radiat1on indudc medical imaging, and radon gas. Radiation can cause cancer ~n most parts of the body, in all animals, ~
although radiation induced solid tumors usually take 10-15 years, and up to 40 years, to become clinically manifest, and
c rl l 11kemias typically require 2 10 yea1s to appear

1 mzmg ra<h tion is a growing source of radiation induced cancers. Prolonged exposure to ultraviolet radiation from the sun
JOI• a anc o•hrr km mahgnancies. Clear eVJdence establishes ultraviolet radiation, especially the medium wave UVB as the
ar om, skin cancers, which arc the most common forms of cancer in the world
ncy radiation from mobile phonl'. electric power transmission, and other s,m1lar so rce~ has also been proposed
ct I re1 tly httlr estaolished evidence of sue ~ lu k

, JI[ r of a genetic mutahor which has a large effect on cancer risk. They cause 1ess than 3-10% of all

thro h the; physical, rath , than chemical, effects on cells

xposure to asbestos, naturally occurnng mineral fibe1<; wl11ct-i are m jor c use of

u both natur,illy occumng and synthetic asbestos hke fibers. such as wull,1sto111te attapulg1te, glass
h. VL s1m1lar cfft els. '
t m 1dr the body (such as tlnough mhaling tiny pieces) and require years of exposure to develop

c, ncu s such as cancer of the breast endometnum prostate ov,.ry._ nd ~ a

ior ,on levels are mostly determined genetically so th•s may at s partly
t o not m o ha,e an} cancer causing genes

v~ s1gmfic n ly ~1gh T · vc s o' estrog and prc,,,,.,.,.,.. rn 1 .t

r ·ast can ven m th absenc of a bre st ancer g

wdifi a ion ut 't nu o single cell

 l NIT 4: ( l'l I COMMUNICA'I ION/CLLI, SIGNALIN(.,
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P pul hon clurin nn rnt11, hi, t11111

(n f lh<' 11nm,11, 11 .1· on. "111 ., y11·,11<•1 11111ti!H·t of n·lls do 1101 g1w 1is1 to cancernus tur111,r
1n01·1· th.111 ,I ,iugh• 111• 111·1i<· a lh•ra l i1111.
J \\ CJn cl1,11ng111,h lwh"·cn l\\o l\'}ll'' of r,1•1wt1c· altPral1ons that might makf' 11s more likely to ,kvelop a particular_ type 1Jf can r
' ' 1' mh rit from 11111 p,11,·nts (gl'1 m h,w 111utaticms) and those that occur during ou1 own lifct1me (~omat 1c mutatH>n'>) .

11Je}umorig,·m•,i, (dl'wlop111enl of a rnahgnant tumor) is a multistep process charac ~·,zPG ay a pwgresswn of perman Ig
Iteration, 111 a ,mglc line of cells, which may occur over the course of many successive cell div J1or and take years to compete
J \.> th1 ,r grneltc changes graduall; occur, the cells in the line become increasingly less responsive to the body's normal r:i~ atol') ach el')
and bettu nbl,· to 1m,1dc normal tissues. According to this concept, tumorigenesis requires that the cell responsible for 1mtiatmg t e ca r
be capable of a large numher of cell divisions.

!he most common -~olid tumors-such as those of the 12!:_east, colon, prostate, and lun_s-arise in e,121thelial tissues th_at a~e norma ~ engaged
ma rc~ati\ el)· high level of cell division. The same is true of le~e~, which-de~ in ra,2idjy dividing blood-formmg tJSsues.

The cells of these tissues can be roughly divided into three groups:

(1) stem cells, which possess unlimited proliferation potential, have the capacity to produce more of themselves, and can give rise to al of the
cell~ of the tissue

(2) progenitor cells, which are derived from stem cells and possess a limited ability to proliferate; and

(3) the d1ffrrcntiatcd end products of the tissue, which generally lack the capability to di VI de.

Tumor-Suppressor Genes and Oncogenes

The genes that have been implicated in carcinogenesis are divided into two broad categories. tumor-suppressor genes and oncogenes.

~ncogenes

They encode proteins that promote the loss of growth control and the conversion of a cell to a malignant state

Most oncogenes act as accelerators of cell division, but they have other roles as well.

Oncogenes may lead to genetic instability, prevent a cell from apoptosis or promote metastasis .

The existence of ~ncogenes was discovered the work on RNA tumor Viruses.

These viruses transform a normal cell mto a malignant cell because they carry an oncogene that encodes a protein that mterferes \\1th the
cell's normal activities.

The turning point in these studies is the discovery of an oncogene called src, earned by an RNA tumor virus called avian sarcoma ,,rus, "as
actually present in the genome of uninfected cells.

So, the oncogene is not a viral gene, but a cellular gene that had become incorporated into the viral genome during a previous infection

Now it is evident that cells possess a variety of genes, referred as protooncogenes, that haYe the potential to sub\·ert the cells own
activities and push the cell toward the malignant state.

The proto-oncogenes encode proteins that have various functions in a cell's normal activities. Protooncogenes can be converted into
oncogenes (i.e., activated) by several mechanisms:

1. ·1 he mutation of gene alters the properties of its product so that it no longer functions normally.

2. Tht· gene can become duplicated many times, resulting in gene amplification and excess production of the encoded protein.

3. A chromosome rearrangement can occur that brings a DNA sequence from a distant site in the genome into close proximity of the gene,
which can either alter the expression of the gene or the nature of the gene product.

Any of thcst• genetic alterations can cause a cell to become less responsive to normal growth controls, causing it to beha,e a 5 a malignant
cell

Oncogenes act dominantly, wluch is to say that a single copy of an oncogene can cause the cell to express the altered phenotype regardless
of whether or not there is a normal , unactivated copy of the gene on the homologous chromosome. '

As long as a cell has its full complement of tumor-suppressor genes, it 1s thought to be protected against the effects of an oncogene.

Most tumors contain alterations m both tumor-~uppressor genes and oncogenes, suggestmg that the loss of a tumor-suppres~or function
within a cell must be accompamed by the conversion of a protooncogene into an oncogene before the cell becomes fully mahgnant.

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Contact: 9052b86470 / 96')2956019 pMnd 1ra1w glr' 11 c
 ~
UNIT 4: CELL COMMUNICA TION/CELL SIGNALING& IMMUNOLO< ~,Y-~,t:__
Mutations in additional genes, such as those encoding cell adhesion mol1•<·ull's OI cxlra<"1·1l11la1 pr ,,1,•,1~1·s may alM, rcquHt,<l I,, f•,re th ' ·' II
acquire the full lifo-thrC'atening phenotype.

__.__ -
Tumor-Suppressor Genes

· th a t rn•·tra1·11
Tumor-suppressor genes act as a cell's brakes; they en.:,o de prolcms c·<·.11 ,.,un,wlh and J>rcvcnt c1·ll'i from hN:oming
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m~gM~. - -
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The transformation of a normal cell to a cancer cell is accompanied by the loss of function of on<· 01 rnort· t tHn<JI supJ,r,••N,r g,-uc
Right now, more than twenty genes have been implicated as tumor suppressors in human s. ~
Included among the genes on the list are those that encode transcription facto_r<; (Tl'53 and Wl'1J, cc!l <,.-ycle rcgulator~ili ., nd Q(,),
components that regulate G proteins, (NF1), a phosphoinosffiae pnospnatasc (PTRN), and a protc:in that r <'.g~ate~ pmt<,w dcgni<~atHin
~L). - -
The most of the proteins encoded by tumor-suppressor genes act as negative regulators of cc:11 proliferation, which IS why their
C
elimination promotes unconti:olle.d.cell growth.

The products of~or-suppressor genes also help maintain genetic stability, which may be a prima1y reason that tum<11s umtain ~ch
an aberrant karyotype. -

The first tumor-suppressor gene to be studied and associated with a rare childhood cancer of the retina of the eyse, called retinobJa.,toma .
The gene responsible for this disorder is nam~ . -

RB is inherited and close examination of cells from children suffering from retinoblastoma revealed that OEC member of the_13u, pair of
homologous chromosomes was missing a small piece from the interior portion of the chromosome.
C
The deletion was present in all of the children's cells-both the cells of the retinal cancer and cells elsewhere in the body-indicating that
the chromosomal aberration had been inherited from one of the parents.
C
Retinoblastoma is inherited as a dominant genetic trait because members of high-risk families that develop the disease inherit one nlJTmal
allele and one abnormal allele. (_
The studies shown that the development of retinoblastoma requires that both copies of the RB gene of a retmal cell be either eliminate cl
or mutated before the cell can give rise to a retinoblastoma.

The RB gene encodes pRB Protein, helps regulate the passage of cells from the G1 stage of the cell cycle into S phase.

The transition from G1 to S is accompanied by the activation of many different genes that encode proteins ranging from D:--;'A polymerases t<;
cyclins and histones.

Among the transcription factors involved in activating genes required for S phase activities are members of the E2F family of
transcription factors, which are key targets ofpRB.

During G1, E2F pro_teins are normally bound to pRB, which prey_ent11 them from activating a number of genes encoding proteins requin:d for
S-ph~~e acti':ili-es (e.g., oycliu E and DNA.Q_o]ymerase q) and the E3.E-pRB complex is associated with the DNA but acts as a gene repressor
~er Than a gene activator.

As the end of G1 approaches, the pRB subunit of the pRB-E2F complex is phosphorylated by the cyclin-dependent kinases that regulate the
G1-S transition.

Once phosphorylated pRB releases its bound E2F, allowing the transcription factor to activate gene expression which marks the cells
irreversible commitment to enter S phase. '
A cell _that loses pRB activity as the result of RB mutation would be expected to lose its ability to inactivate E2F, thereby removing certain
restramts over the entry to S phase.

The import?nce of pRB as a negative regulator of the cell cycle is demonstrated by the fact that DNA tumor viruses (including adenoviruses
human pap1lloma Virus, and SV40) encode a protein that binds to pRB, blocking its ability to bind to E2F '
(
PS3
~
The PE protein c~ded by TP53 ge~e, having a molecular mass of 53,000 daltons.
(
The TP53 is the most~~only mutate_~ gene in human cancers; approximat~ half of all human tumors contain cells "''th
~utations otckletion.§..iJu>oth alleles of the TP53 ~ene. - - - - - _ 1 _£?mt

A.ifp53 is a ~ranscription factor that activates the expression of a large number of genes involved in cell c ·cle
7·• apoptos1s. • • • d
Y regu 1at10n an

There are six mutations most commonly found to disable P53 in human cancers· all of them map in the
interacts with DNA. ' regmn °f the protem
.
that

hclpBIOTECH~ Academy Hyderabad I CSIR, GATE, SET, MSc CSIR JRF/NET 2024 in Life Science.'>
Contad: 9052686470 / 965_956019 I pnun,Lra1 g , , c:
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prr 1111111f th p211;1 111 1 ,11 IIV 1tul, 111d p,,, 'fl
d 1111 ,, l,, foil 11 111111 11t JJN/\ I pl 11 11l 11111
~
I h 1\1 b , 11 rn utnt, d ,, that tht 1r pr1,rlu<.:t 1 1111 11,ngcr fu,wtrr,nal, th· u II can no or r I'
,11 lrol I hat JJJc\·1rll 11 frri rn cntlnng S ph,, wh, n 111 n1,t prcp.ir cl lo dr, <1

1 ,d lo tic 1nr1duct 11,n f1 f abn,mnal cell that have th,· pr,tcnt 1al 1,, 1,cu,mc malign:mt

1 an d1r tag n t1cally damaged cell along a pathway that !rad~ to death 1,y apoptosi,;, thc rcl,y nddmg the body of c II
nt pot nil 1

cdl tO\\ar<l tell 9clc arrc t rir apopto i apparently depends on the type of posttranslat1onal rnorl1ficat1011s t,, ½htch 11

I n I thought to direct a r;cll into ap1Jpt<>s1s as the result of several events, including the act 1vatwn of exp ression of the HAX
n ded product (Bax) initiate ap<>.I?tr;,;is.

ofbmdmg d1rectlyt,J c.-veral member of the Hcl -2 fam1lypwteins ma manner that ~tim ulates apoptosis.

ab1 1ty to trigger apoptr, , , P5'1 plays a pivotal role m treatment of cancer by radiation and chemothera py.

nd1cate that P'i3 al o c.:rmtrols SJgnalmg pathways that lead to cellular c,enec,cence, anot her mecha nism that has evolved as a
top wayward cell from developing into malignant tumors.

apoptot1c eel , ene cent cell remam ahve and metabolically active but they are permanently arrested in a nondivid ing state, as
1fied by the ene cent mdanocytes found in moles.

n can be triggered man <ith IW!Se normal cell by the experimental act ivat ion of an oncogene, suc h as Rae,

leadmg to enc cence requires expression of a tu mor suppressor gene calkd INK4a , which 1s often disab led in human

two eparate tumor- uppressmg proteins· p161 which is an inhibitor of cycli n depe ndent kinases, and ARF, which stabilizes

Other Tumor-Supprec;sor Genes

tated APC gene are found not only in inherited fo rms of colon ca ncers, but also in up to 80 percent of sporadic colon tumors, suggesting
t g n pays a maJor role m the development of this disease.

encoded by the APC gene binds a number of different proteins, and its mechanism of action is complex . In its best studied role,
ppre the Wnt pathway, which activates the transcrip tion of genes (MYC and CCND1) that promote cell proliferation .

BRC'A1 and BRCA2 genes are responsible for the majority of the inherited cases of breast cancer. BRCA mutations also predispose a
oman to the de\e opment of ovarian cancer, which has an especially high mortality rate.
Oncogenes

Oncogenes are derived from protooncogenes, which are genes that encode protc•ins
ors-Q having a functio n in the normal cell.
Si;
'~owth factor receptors
•ec;;ptu (H£R2) Most known protooncogenes play a role in the control of ceU growth and
division .

The oncogene mutated most freque ntly in human tumors is RAS , which encodes a GTP
binding protein (Ras) that functions as an on-off switch for a number of key signaling
pathways controlling cell proliferation.

Oncogenic RAS mutants typically encode a protein whose GTPase activity cannot be
stimulated, which leaves the molecule in an active GTP-bound form , sending
continuous prol ife ration signals along the pathway.

Oncogenes - Growth Factors or Their Receptors

'I he cancer-causing simian sarcoma virus contained an oncogene (sis) derived from the
cellular gene for platelet-derived growth facto r (PDGF) a protein present in
human blood.

Cultured cells that are trnnsformed with this Virus secrete large amounts of PDGF into
the medium , which causes the cells to proliferate in an uncontrolled fashion .
Overexpression of PDGF has been implicated in the development of brain tumors

CSIR JRF/ NET 2024 in Life Sciences

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(gliomas).
Th · · d . EGF eccptor that is missing part of the
e a,1an ervthrnbl.1~tmas rn ns, w;1s found lu l'arry an oncogene (crbB) that enco cs an , r II t"tI uvely that 15
extracellular <lo111,1in of the proll'lll that hmcls the growth factor. This altered version of the receptor stimulates the ce cons u • '
regardless of I\ hPthcr or not lhl' growth factor 1s present in lhe medium.
· f h · th · J embranes than do normal cells. The
Most conunonh. the malignant cells contain a much larger number o l e receptors m e1r P asma m st1. 1 t d t 0
presencP of excess l'Cceptors makes the cells sensitive to much lower concentrations of the growth factor, and thus, they are mu a e
di,·ide under cond1llons that would not affect normal cells.
A number of studies suggest that mutations in EGFR occur commonly in lung cancers from patients who have never smoked, but are not
found in lung cancers from smokers.
Oncogenes - Cytoplasmic Protein Kinases Overactive protein kinases function as oncogenes by generating signals that lead to
mappropriate cell proliferation or survival.
th
C
Raf, for example, is a serine-threonine protein kinase that heads the MAP kinase cascade, the primary growth-controlling signalling pa way
in cells (Check cell signalling).
The mutations to Ras, Raf into an enzyme that remains in the on position are most likely to convert the proto-oncogene into an oncogene
and contribute to the cell's loss of growth control. C
Raf is most closely linked to melanoma, where BRAF mutations play a causative role in the development of approximately 70 percent of
these cancers.
The first oncogene to be discovered, SRC, is also a protein kinase, but one that phosphorylates tyrosine residues on protein substrates rather
than serine and threonine residues.
Transformation of a cell by a src-containing tumor virus is accompanied by the phosphorylation of a wide variety of proteins.

Oncogenes - Nuclear Transcription Factors

Probably the best studied oncogene whose product acts as a transcription factor is MYC.
(
Myc is normally one of the first proteins to appear when a cell in this quiescent stage (Go) has been stimulated by growth factors to
reenter the cell cycle and divide .
C
.Myc regulates the expression of a huge number of proteins and miRNAs involved in cell growth and proliferation. C
When MYC expression is selectively blocked, the progression of the cell through G1 is blocked.
The MYC gene is one of the proto-oncogenes most commonly altered in human cancers, often being amplified within the genome or (
rearranged as the result of a chromosome translocation.

One of the most common types of cancer among populations in Africa, called Burkitt's lymphoma, results from the translocation of a (
l\,fYCgene to a position adjacent to an antibody gene The disease occurs primarily in persons who have also been infected with Epstein-
Barr virus.
(
Oncogenes - Apoptosis Apoptosis is one of the body's key mechanisms to rid itself of tumor cells at an early stage in their progress10n
t0\1ard malignancy.

The oncogene most closely linked to apoptosis is BCL-2, which encodes a membrane-bound protein that inhibits apoptosis.

Like MYC, the !)roduct of the BCL-2 gene becomes oncogenic when it is expressed at higher-than-normal levels, as can occur when the gene
1s translocated to an abnormal site on the chromosome.

MicroRNAs - Cancer

The micro RX A.~ are tmy regulatory RNAs that negatively regulate the expression of target mRN'As.
r-
f
lt was reported that t_he locus t_hat encodes two microR.t'\As, miR-15a and miR-16, was either deleted or underexpressed in most cases
of chrome l;mphocytic leukemia.

It was subsequently shown that these two miR.t'\As act to inhibit expression of the mR.'\A that encodes the antiapoptotic t · B 1-
known proto-oncogene. pro em c 2, a

Tn the absence of the miRNAs, the oncogenic Bcl-2 protein is overexpressed, which promotes development of leukemia.

The express1Q!!_Q_~_~o of the most i_mpQ._rtant h_uman o_Qc~es_,_ RAS and MYC, ha\·e also been shown to be inhib 1•t db . •n,•A
namely, let-7, which wastfie•ffrst m1R.i."-:A to be discovered. .._ - e ) an ffiln.,, ·

Some m1R.i."'-;As act more like on<;Qg~than tumor suppressor.:?..

Therapeutic Approaches

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 UNIT 4: CELL COMMUNICATION/CELL SIGNALING& IMMUNOLOGY
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1m1 ng limited curative value for most advanced cancers. - -

The anticancer strategies can be divided into three groups:

(1) Immunotherapy ✓
( 2) Inh!b!t!ng the Activity of Cancer-Promoting Proteins and ./
(3) Inh1bitmg the Formation of New Blood Vessels (Angiogenesis) ..._,,,

1. lmmunotherapy

1\vo broad treatment strategies involving the immune system have been pursued: passive immunotherapy and active immunotherapy.

Pas~bive _immunotherapy is an approach that attempts to treat cancer patients by administering antibodies as therapeutic agents. These
anti odies recognize and bind to specific proteins on the surface of the tumor cells being targeted.

Hferceptin is a humanized antibody directed against a cell-surface receptor (Her2) that binds a growth factor that stimulates the proliferation
o breast cancer cells.

Herceptin is thought to inhibit activation of the receptor by the growth factor and stimulate receptor internalization.

To date, the m~~tive humanized antibody is Rituxan, for the ~tment of,non- Hodgkin's B-cell lymphoma.

~tuxan b~d~ to a cell-surface protein (CD20) that is present on the malignant B cells in approximately 95 percent of the cases of this
disease. Bmdmg of the antibody to the CD20 protein inhibits cell growth and induces the cells to undergo apoptosis.

Others include

Vectibix, which is directed against the EGF receptor, has been approved as a single- agent treatment of EGFR-expressing metastatic colon
cancer.

Inhibiting the Activity of Cancer-Promoting Proteins

Cancer cells behave as they do because they contain proteins that are either present at abnormal concentration or display abnormal activity.

In many cases, the growth and/or survival of tumor cells is dependent on the continued activity of one or more of these deviant proteins.

' This dependency is known as "oncogene addiction."

If the activity of one of these proteins can be selectively blocked, it should be possible to kill the entire population of malignant cells.

Below table gives some of the agents tested against cancer.

Inhibiting the Formation of New Blood Vessels (Angiogenesis)

Angiogenesis, is as process where a tumor grows in size, it stimulates the formation of new blood vessels.

Blood vessels are required to deliver nutrients and oxygen to the rapidly growing tumor cells and to remove their waste products. Blood
vessels also provide the conduits for cancer cells to spread to other sites in the body.

Cancer cells promote angiogenesis by secreting growth factors, such as VEGF, that act on the endothelial cells of surrounding blood vessels,
stimulating them to proliferate and develop into new vessels.

Just as there are stimulants of angiogenesis, there are also inhibitors. Naturally occurring inhibitors, such as endostatin and
thrombospondin, have been identified, but most angiogenic inhibitors have been developed by biotechnology companies.

Dru Tar et Mechanism of action

Glee,·ec BCR-ABL, KIT, PDGFR Tyrosine kinase inhibitor
Iressa EGFR Tyrosine kinase inhibitor
Tarcen1 EGFR Tyrosine kinase inhibitor
Sutent VEGFR, PDGFR, KIT Tyrosine kinase inhibitor
Tykerb EGFR, HER1 Tyrosine kinase inhibitor
Nexavar BRAF, EGFR, EGFR Kinase inhibitor

Velcade proteasome Inhibits protein degradation

Winza HDACs Inhibits histone acetylation (epigenetic effect'?)

Torisel mTOR Blocks cell-survival pathway

Tamoxifen, Raloxifene Estrogen receptor Blocks estrogen action

Arimidex, Arornasin Aromatase Inhibits S}nthesis of estrogen

Gena sense BCL-2 Inhibits synthesis of this proapoptotic protein

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AIT-737 BCLXL Inhibits this proapoptotic protein

- .. HSP90 Inhibits this molecular chaperone ~
~
Nutlfnl. RITA P53 Inhibits p53-MDM2 interaction
PRIMA I P53 Restores activity of mutant P53
Inhibits this transcription factor that is activated by hypoxia
~
PX-478 HIF-1
BSI 201 PARP-1 Inhibits this enzyme involved in DNA repair
Decitabine DNMT Inhibits DNA methylation
~
1bese mclude antibodies and synthetic compounds directed against integrins, growth factors, and growth-factor receptors.

Most amportantly, tumors treated with these inhibitors did not become resistant to repeated drug application.
~
Inhibitors of angiogenesis, however, target normal, genetically stable endothelial cells, which continue to respond to the presence of these
ag

There are several other reasons that make angiogenesis inhibitors a promising therapy: they should not interfere with normal physiologic
a bes because angiogenesis is not a required activity in a mature adult; they act on cells lining the bloodstream, which are directly
ible to bloodbome drugs; and they should be broadly effective against many different types of tumors, which are presumed to employ
the same mechanism of angiogenesis.
To date the most promising results have been obtained with a humanized antibody (Avastin) that is directed against VEGF, the endothelial
c:e growth factor that is overexpressed in most solid tumors.

A tin blocks VEGF from binding to and activating its receptor, VEGFR.