THE HALLMARKS OF CANCER

Presented by :

Shamanth Neralagundi H.G

Research Scholar

What is cancer?

Abnormal cell growth (neoplasia)

Tumour divided into two types

Benign: slow growth, non-invasive, no metastasis

Malignant: rapid growth, invasive, potential for

metastasis

Cancers originate from a single cell

What causes the mutations that lead to cancer?

Viruses: HPV --> cervical cancer

Bacteria: H. pylori --> gastric cancer

Chemicals -->Nicotine --> lung cancer

UV and ionizing radiation --> skin cancer

Mutagens

•Viruses: insertional mutagenesis

•Chemicals: DNA adducts

•UV and ionizing radiation: single

and double strand DNA breaks

What types of genes get mutated in cancer?

•Oncogenes are activated

Normal function: cell growth, gene

transcription

•Tumor suppressor genes are inactivated

Normal function: DNA repair, cell cycle

control, cell death

What are the differences in the

features of normal and cancer cells

Hallmarks of Cancer

Six fundamental changes

1. Self sufficiency in growth factors

2. Insensitivity to growth-inhibitory

signals

3. Evasion of apoptosis

4. Limitless replicative potential

5. Sustained angiogenesis

6. Ability to invade and metastasize

Self sufficiency in growth signals

Dependence on growth signal can be seen in normal cells but

in cancer cells they have got autonomy in synthasis of

growth singnals

Receptors over expression may enable the cancer cell to

become hyperrseponsive to ambient level of growth factors

(ERG-R/erbB) is upregulated in stomach ,brain and breast

tumors

Ligand independent signaling can be achieved through

structural alteration of recptors

Ras protiens are present in structurally altered forms that

enable them to release a flux of mitogenic signals into cells

Intracellular signalling

Growth factors

Growth factor receptors

Cell wall

Insensitivity to growth-inhibitory signals

Within normal tissue ,multiple antiproliferative signals

operate to mantain cellular quiescence and tissue

homeostasis

Cells monitor their external environment during G1

phase on the basis of signals decides whether to

proliferate or to be quiescent or to enter a post mitotic

state

Disruption of the pRB pathway liberates E2Fs and thus

allows cell proliferation

Over expression of oncoprotien can reverse the process

,there by imparing differentiation and promoting

growth

Evading Apoptosis

Tumors cannot enlarge beyond 1-2 mm thicknessunless they are vascularized, hypoxia will induceapoptosis by activation of p53 .

Angiogenesis is required for tumor growth &metastasis.Tumor-associated angiogenic factors may be producedby the tumor or by inflammatory cells

P53 inhibit angiogenesis by stimulation ofanti-angiogenesis molecules

VEGF is under the control of RAS oncogene .Proteases are involved in regulating angiogenic &antiangiogenic factors

Development of Sustained Angiogenesis

VEGFRFGFR PDGFR

Smooth

muscle Endothelial Blood vessel

Oxygen and

nutrientsBlood vessel

The formation and maintenance of new

blood vessels (angiogenesis) plays a critical

role in tumour growth.

New blood vessels supply the cancer cells

with oxygen and nutrients, allowing the

tumour to grow.

Angiogenesis is mediated principally

through vascular endothelial growth

factor (VEGF)

Other growth factors also play a role, e.g.:

• Fibroblast growth factor (FGF)

• Platelet-derived growth factor (PDGF)

Angiogensis activator and inhibitors

Ability to Invade & Metastasize

Tumor cells binds to leukocytes, this protect them from

host defense mechanisms

Tumor cells adhere to vascular endothelium & pass

through Basement membrane

Site of extravasations & Meyts depends on:

-Blood & Lymphatic supply

-Organ tropism/adhesion molecules

Function of E-cadherin is lost ,which serves as a

widely acting suppressor of invasion

Most normal human cells have a capacity of 60-70

doubling, after the cell will enter non replicative

senescence & result in shortening of telomeres at the

end of chromosome & loss of telomeres beyond a

certain point will lead to massive chrosomal

abnormalities & death

In order to develop tumor, need to maintain cells i.e.

avoid cell senescence

This is done by enzyme TOLEMERASE which

maintain chromosome length

85-95% of cancer have up regulation of enzyme

telomerase

Limitless Replicative Potential

Emerging Hallmarks

Deregulating cellular energetics

Cancer cells environment

Targeting the tumour

Summary

•Cancer is a disease of Division, growth and spread

•It has a number of causes many of them

preventable

•The survival of the patient is determined by the

stage of the disease, the earlier the detection or the

smaller the tumour the better the survival