CARCINOGENESIS – I
(MOLECULAR BASIS)
Presented by,
Dr.Lakshmi S Anand
II MDS
NORMAL BODY CELLS GROW, DIVIDE AND
DIE IN AN ORDERLY FASHION.
Cancer cells
are different
because they
do not
die, they just
continue to
grow and
divide in a
disorderly
fashion.
"A neoplasm is an abnormal mass of tissue, the growth of which
exceeds and is uncoordinated with that of the normal tissues, and
persists in the same excessive manner after cessation of the stimulus
which evoked the change”
- WILLIS
SOME FACTS..........
 Cancer is the second leading cause of death globally.
ORAL CANCER
INDIA
New cases: 11,57,294
Death : 7,84,821
(GLOBOCAN 2018)
 Kerala – 2016
Crude cancer rate is highest
135.3/100000population
“IF YOU LIVE IN KERALA, YOU ARE TWICE AS LIKELY TO GET CANCER AS A
JHARKHAND RESIDENT”
- MEDIBULLETIN september 2018
When will there be a cure for cancer????????????
• PATHOGENESIS
•MOLECULAR BASIS
ORIGIN
Hippocrates – Greek words carcinos/carcinoma
Neoplasm – new growth
Oncology
There are two types of tumors:
Malignant tumors : spread to other areas in the body.
Benign tumors: stay in one place.
Basic components:
•Parenchyma
•Stroma
Teratoma : tumor which contain mature/immature cells representative of more than
one germ layer
Hamartoma :A benign (noncancerous) tumor-like growth consisting of a disorganized
mixture of cells and tissues normally found in the area of the body where the growth
occurs
Choristoma : tumor-like mass consisting of normal cells in an abnormal location
CHARACTERISTICS OF BENIGN & MALIGNANT
NEOPLASM
Differentiation & anaplasia
Rate of growth
Local invasion
Metastasis
DIFFERENTIATION
show wide range of parenchymal cell differentiation
ANAPLASIA
Lack of differentiation( both structural and functional)
Microscopic features of anaplasia
• pleomorphism : variation in the size and shape of cells and cell nuclei
•Hyperchromatic nuclei
•Increased nuclear cytoplasmic ratio
•Increased and atypical mitosis
•Loss of polarity
•Bizarre cells
•The more anaplastic a tumor is,the more aggressive it is.
RATE OF GROWTH
Benign tumors: slow growth, influenced by blood supply and pressure constraints
Malignant tumors: rate of growth is inversely corelated with level of differentiation
LOCAL INVASION
• Benign tumor : remains localised at its site of origin. Doesnot have the capacity to
infiltrate ,invade or metastasize to distant site.
•Malignant tumor: grow by infiltration,invasion,destruction,and penetration of
surrounding tissue
METASTASIS
o secondary implants of a tumor that are discontinuous with the primary tumor and
located in remote areas.
oProperty of malignant neoplasm
o3 pathways: seeding within body cavities
lymphatic spread
hematogenous spread
Seeding within the bodycavities:
Seeding of body cavities and surfaces may occur whenever a malignant neoplasm
penetrates into a natural body cavity.Most often involved is the peritoneal cavity ,
but any other cavity—pleural, pericardial, subarachnoid, and joint space—may be
affected. Such seeding is particularly characteristic of carcinomas arising in the
ovaries.
LYMPHATIC SPREAD
oTransport through lymphatics is the most common pathway for the initial dissemination
of carcinomas ,and sarcomas may also use this route.
oTumors do not contain functional lymphatics, but lymphatic vessels located at the
tumor margins are apparently sufficient for the lymphatic spread of tumor cells
oThe pattern of lymph node involvement follows the natural routes of lymphatic
drainage.
oBecause carcinomas of the breast usually arise in the upper outer quadrants, they
generally disseminate first to the axillary lymph nodes.
oCancers of the inner quadrant may drain through lymphatics to the nodes within the
chest along the internal mammary arteries. Thereafter the infraclavicular and
supraclavicular nodes may become involved
Carcinomas of the lung arising in the major respiratory passages metastasize first to
the perihilar tracheobronchial and mediastinal nodes.
Local lymph nodes, however, may be bypassed—"skip metastasis"—because of
venous-lymphatic anastomoses or because inflammation or radiation has obliterated
lymphatic channels.
A sentinel lymph node is defined as "the first regional lymph node that receives
lymph flow from the primary tumor”
Biopsy of the sentinal lymph node allows determination of the extent of spread of
the tumor and can be used to plan treatment.
HEMATOGENOUS SPREAD
Hematogenous spread is typical of sarcomas but is also seen with carcinomas.
Arteries, with their thicker walls, are less readily penetrated than are veins. Arterial
spread may occur, however, when tumor cells pass through the pulmonary capillary
beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves
give rise to additional tumor emboli.
With venous invasion, the blood-borne cells follow the venous flow draining the site
of the neoplasm.
liver and lungs are most frequently involved secondarily in such hematogenous
dissemination.
CARCINOGENESIS
 a process bywhich a normal cell is transformed into a malignant cell and
repeatedly divides to become a cancer
Multistep process resulting from accumulation of multiple mutations.
Non-lethal genetic damage lies at the heart of carcinogenesis.
 Genetic damage (or mutation) - environmental agents
1-The growth promoting protooncogenes.
Four classes of normal regulatory genes are
the principle targets of genetic damage
2-The growth inhibiting tumor suppressor
genes.
3-Genes that regulate programmed cell
death (apoptosis).
4-Genes involved in DNA repair.
24
Proto-oncogene : normal cellular genes usually involved in cell growth and cell
division
Oncogene : a protooncogene that has been mutated /overexpressed. Results in a
dominant gain of function phenotype
Tumor suppressor gene: normally restrain cell growth,loss of function results in
unregulated growth
THEORIES OF CARCINOGENESIS
Somatic mutation theory
Tissue field organisation theory
SOMATIC MUTATION THEORY
Cancer is derived from a single somatic cell that successively has accumulated
multiple DNA mutations
Mutations occur on genes that control cell proliferation and cell cycle
The default state of cell proliferation in metazoa is quiescence
Carcinogenesis takes place at the cellular or subcellular hierarchical level of
complexity
TISSUE FIELD ORGANIZATION THEORY
Carcinogenesis is a problem of tissue organisation
Proliferation is the default state of all cells
Carcinogenic agents destroy the normal tissue architecture thus
desrupting the cell –cell signalling and compromising genomic
instability
Carcinogenesis takes place at the tissue hierarchical level of
complexity
HALLMARKS OF CANCER
Posed by Douglas Hanahan and Robert Weinberg in 2000
Douglas Hanahan
Robert A. Weinberg
As refined by Douglas Hanahan and Robert Weinberg in 2011
1.SELF SUFFICIENCY IN GROWTH SIGNALS
•Growth factors
•Growth factor receptors
•Signal transduction genes
•Nuclear transcription factors
•Cell cycle regulators
FUNCTIONS OF CELLULAR PROTO-ONCOGENES
1. Secreted Growth Factors
2. Growth Factor Receptors
3. Cytoplasmic Signal
Transduction
Proteins
4. Nuclear
Proteins:
Transcription
Factors
5. Cell Growth
Genes
17
GROWTH FACTORS
• Most soluble growth factors are made by one cell type and
act on a neighboring cell to stimulate proliferation paracrine action
• Cancer cells, however, acquire the ability to synthesize the
same growth factors to which they are responsive,
generating an autocrine loop
• Note:
– In most instances the growth factor gene itself is not altered or mutated
– They are forced to secrete large amounts of growth factor
GROWTH FACTORS
Increased growth factor production is not sufficient for neoplastic transformation But, growth factor driven
proliferation may contributes to spontaneous or
induced mutations in the proliferating cell population
GROWTH FACTOR RECEPTORS
• GF receptors are transmembrane proteins with an
external ligand-binding domain and a cytoplasmic
tyrosine kinase domain
• GF binding results in dimerization of and
tyrosine phosphorylation of several substances
down the signalling cascade
• The oncogenic versions of these receptors are
associated with constitutive dimerization and
activation without binding to the growth factor
Growth factor receptors can be constitutively activated in
tumors by multiple different mechanisms:
– Mutations
– Gene rearrangements
– Overexpression
Example: RET oncogene
In MEN-2A: mutations in the RET extracellular domain cause
constitutive dimerization and activation, leading to medullary thyroid
carcinomas and adrenal and parathyroid tumors.
In MEN-2B: mutations in the RET cytoplasmic domain alter the
substrate specificity of the tyrosine kinase and lead to thyroid and
adrenal tumors without involvement of the parathyroid
Protooncogenes
MOA
Associated
human tumors
EGF receptor family
ERB1,2
Overexpression
SCC
FMS like tyrosine
kinase 3
FLT3
Amplification
Breast ,ovary
Receptor for
neurotrophic
factor
RET
Point muat
tation
MEN 2A 2B,
MTC
PDGFR
PDGFR B
Overexpression
Leukemia
Receptor for stem
cell factor
C-KIT
Point mutation
GIST,
Seminomas,
leukemias.
Category
Growth factor
receptors
SIGNAL-TRANSDUCING PROTEINS
• Most such proteins are strategically located on the inner
leaflet of the plasma membrane, where they receive signals
from outside the cell (e.g., by activation of growth factor
receptors) and transmit them to the cell's nucleus
Eg: RAS family of guanine triphosphate (GTP)- binding
proteins (G proteins)
ALTERATIONS IN NONRECEPTOR TYROSINE
KINASES
• Non-receptor-associated tyrosine kinases normally
function in signal transduction pathways that regulate
cell growth
• ABL protooncogene
• Mutations take the form of chromosomal translocations or
rearrangements that create fusion genes encoding
constitutively active tyrosine kinases
ABL-BCR FUSION IN CML
Protooncogenes
MOA
Associated
human tumors
GTP binding
K RAS
H RAS
N RAS
Point mutation
Colon pancreas
Bladder kidney
Hematological
Non receptor
tyrosine kinase
ABL
Translocation
CML
RAS Signal
transduction
BRAF
Point mutation
Melanomas
WNT signal
pathway
B catenin
Point mutation
HCC
Category
Proteins involved in
signal transduction
TRANSCRIPTION FACTORS
• A host of oncoproteins, products of the MYC, MYB, JUN,
FOS, and REL oncogenes, are transcription factors that
regulate the expression of growth-promoting genes, such as
cyclins
• Of these, MYC is most commonly involved in human tumors
CELL CYCLE REGULATORS
Category
Nuclear regulatory
proteins
Transcriptional
activators
Protooncogenes
MOA
Associated
human tumors
C MYC
N MYC
L MYC
Translocation
} Amplification
Burkitts
Neuroblastoma,
small cell
carcinoma lung
Cyclin D
Translocation,
amplification
Mantle cell
lymphoma, breast
& oesophagus
Cyclin E
Overexpression
Breast ca
CDK4
Amplification
glioblastoma
Cell cycle regulators
Cyclins
CDK
2. INSENSITIVITY TO GROWTH INHIBITORY
SIGNALS
TUMOR SUPPRESSOR GENES
Normal function - inhibit cell proliferation
Absence/inactivation of inhibitor --> cancer
3.EVASION OF APOPTOSIS
Apoptosis in normal cell is guided by cell
death receptor CD95/Fas (extrinsic
pathway) & by DNA damage (Intrinsic
pathway).
The integrity of the outer mitochondrial
membrane is regulated by pro- apoptotic
and anti- apoptotic members.
Reduced
CD95
level
Binding of FLIP
inactivates
death- induced
signalling
complex
Loss of P53 leading to
reduced levels of BAX
Reduced cytochrome c
from
mitochondria due to
increased BCL2
Loss of APAF-1
*FADD- Fas associated via death domain,
*IAP-inhibitors of apoptosis
*APAF-1- Apoptotic peptidase activating
factor-1
IAP inhibits
caspases
4.GENOMIC INSTABILITY
Normally p53 gene is responsible for
detection and repair of DNA damage.
 Defects in 3 types of DNA-repair systemsMismatch repair, nucleotide excision
repair and recombinant repair,
they contribute to different types of
cancers.

1) Hereditary
non-polyposis colon
cancer(Lynch Syndrome)It is a familial carcinoma of the colon.
There is a defect in genes involved in DNA- Mismatch
repair
.
pair
mismatch re
2) Xeroderma PigmentosumDefect in Nucleotide excision repair
system.
3) Ataxia telangiectasia- Hypersensitivity to
DNA damaging agent such as ionizing agents
5.
Limitless Replicative
Potential:Telomerase
After each mitosis(cell doubling) there is progressive shortening
of telomeres which are the terminal tips of chromosomes.
 However , it has been seen that after repetitive mitosis for a
maximum of 60-70 times, telomeres are lost in normal cells and
the cells cease to undergo mitosis.

Replication
of
somatic cells, which
do not express
telomerase, leads to
shortened telomeres.
-In the presence of
competent
checkpoints, cells
undergo arrest and
enter nonreplicative
senescense.
-In the absence of
checkpoints, DNA repair
pathways are
inappropriately activated,
leading to the fomation
of dicentric
chromosomes. At
mitosis, the dicentric
chromosomes are pulled
apart at anaphase,
resulting in new double
stranded DNA breaks.
This Bridge- fusion
breakage cycle
repeats and produces
mitotic catastrophe
and cell death.
-Re-expression of
telomerase allows
the cells to escape
the bridge-fusionbreakage cycle, thus
promoting their
survival.
6.DEVELOPMENT OF SUSTAINED ANGIOGENESIS
Tumor cells cannot enlarge beyond 2 mm of size unless they are
vascularized.
required for normal metabolism- oxygen and nutrients
Dual effects: Perfusion supplies required nutrients & oxygen.
Newly formed endothelial cells secreates GF and contributes for growth
of new tumor cells.
Angiogenic switch involves production of angiogenic factors& loss of anti
angiogenic factors.
Tumor associated angiogenic factors ( VEGF & FGF )are
produced by tumor cells & inflammatory cells (macrophages)
which infiltrate tumors.
Additionally Mutational inactivation of both p53 alleles, causes
↓ in antiangiogenic factors like thrombospondin – 1 & ↑ in VEGF
& Hypoxia inducible factor – 1 ( HIF – 1)
7.INVASION AND METASTASIS :
Biologic hallmarks of malignant tumors.
Invasiveness is a reliable feature that differentiates malignant from
benign tumors.


Metastasis – tumor implants discontinuous with the primary
tumor.
Dissemination occurs with one of the three pathways





a. Hematogenous spread
b. Lymphatic spread
c. Direct seeding of body cavities or surfaces.
Metastatic cascade can be divided in 2 phases :
i. Invasion of extracellular matrix
ii. Vascular dissemination and homing of tumor cells
-
a)Invasion of ECM
Active process involving the following
steps.
1. Loosening up of the tumour cells
from each other.
Downregulation of E Cadherin.
2. Degradation of ECM
proteolytic enzymes
MMP, Cathepsin D, UPA.
3. Attachment of tumor cells to novel
ECM proteins
Loss of adhesion in normal cell induces
apoptosis.Tumor cells
resistant to apoptosis & additionally
matrix modified. MMP2, MMP 9
produces novel sites that bind to
tumor cells and stimulates migration.
4. Migration:
Final step of invasion, tumor propells
through the BM. Complex multistep
process . Cells attach at the leading
edge, detach from the matrix at
trailing edge and contract the actin to
move forward.
8.REPROGRAMMING ENERGY METABOLISM
9.EVASION OF THE IMMUNE SYSTEM
10.TUMOR PROMOTING
INFLAMMATION
•Tumor associated inflammation aid in tumor growth by suppling the tumor
microenvironment with
•Growth factors
•Pro angiogenic factors
•Survival factors
THERAPEUTIC TARGETING OF HALLMARKS OF
CANCER
CONCLUSION
Cancer is a broad term to describe a large variety of diseases, the common feature
of which is uncontrolled cell division .Carcinogenesis is a complex process which
involves many mechanisms acting together / independently. Knowledge about the
underlying molecular pathology helps the research field to find targeted therapies
that can resolve the problem completely.
References
1. Robins and Cotran Pathologic Basis of Diseases, 7th Edition
2. Devi PU. Basics of carcinogenesis. Health Adm. 2004;17(1):16-24.
3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. cell. 2011 Mar
4;144(5):646-74.
4. Malarkey DE, Hoenerhoff M, Maronpot RR. Carcinogenesis: Mechanisms and manifestations.
InHaschek and Rousseaux's Handbook of Toxicologic Pathology 2013 Jan 1 (pp. 107-146).
Academic Press.
5. Sonnenschein C, Soto AM. Theories of carcinogenesis: an emerging perspective. InSeminars in
cancer biology 2008 Oct 1 (Vol. 18, No. 5, pp. 372-377). Academic Press.
6. Sigston EA, Williams BR. An emergence framework of carcinogenesis. Frontiers in Oncology. 2017
Sep 14;7:198