hall marks of cancer
Post on 15-Jul-2015
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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
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
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
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)
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
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