14 march seminar

Overview of cancer

Point to be covered1. Overview of cancer

2. Types and reason of cancer

3. Basic idea about progression of tumor

4. Cell division

5. Cell division regulation

6. Genetic instability

7. Mutation

8. Invasion

9. Angiogenesis

10. Metastasis

11. Grading and staging

12. Treatment

Cancer

• Cancer is a large group of diseases characterized by uncontrolled growth and spread of abnormal cells

• Cancer cells:– Lose control over growth and multiplication

– Do not self-destruct when they become worn out or damaged

– Crowd out healthy cells

Cancer• Cancer cells reproduce every 2-6

weeks

• Size of cancer cells:

One million cancer cells = head of a pin

One billion cancer cells = a small grape

• Five-year survival rate (starting from the time of diagnosis)

2-6 weeks

2-6 weeks

2-6 weeks

Carcinogens• Ionising radiation – X Rays, UV light

• Chemicals – tar from cigarettes

• Virus infection – papilloma virus can be responsible for cervical cancer.

• Hereditary predisposition – Some families are more susceptible to getting certain cancers. Remember you can’t inherit cancer its just that you maybe more susceptible to getting it.

LifestyleLifestyle

EnvironmentEnvironment

Family Family HistoryHistory

Types Cancers

– Carcinoma: epithelial cells

– Adenocarcinoma: glandular tissue

– Sarcoma: connective tissue

– Lymphoma: lymph tissue

– Leukemia: blood forming tissue (marrow)

– Gliomas: cancer of brain glial cells

Carcinomas (cells that cover internal and external body surfaces)

Lung

Breast

ColonColon

BladderBladderProstate Prostate (Men)(Men)

LeukemiaLeukemia(Blood Cells)(Blood Cells)

LymphomasLymphomas(Lymph nodes)(Lymph nodes)

SarcomasSarcomasCells in supportive tissues – bones & muscles

Proliferation and differentiation

• Increase in the cell number with exact passages of genetic information to their daughter cells

• Different kinds of cells with the specialized morphology, metabolism and physiological functions from the cells of the same origin.

Hypertrophy, hyperplasia, Dysplasia vs Neoplasia

Tumor invasion of the basement membrane• Benign lesion characterized by the continuous

basement membrane, that separate neoplastic epithelium from the stroma

• Malignant tumor have loss of basement membrane around tumor cell in stromal compartment

Benign and Malignant Tumors

Normal cell

Inactivation of tumor suppressor gene

DNA damage

Activation of proto-oncogene

Unregulated proliferation Decreased apoptosis

Mutation in somatic cells

Alteration of apoptosis gene

Failure of DNA Repair

Tumor progression

Malignant neoplasm

Clonal expansion

Invasion Metastasis

Acquired DNA damaging agent

i.e. chemical, radiation, virus mutation i.e. genes

affecting DNA repair and apoptosis

pathway

Successful DNA repair

•Angiogenesis•Escape from immunity Additional mutation

Phases of the cell cycleCell cycle have two phase

(1) S phase (Non-division phase)

(2) Division phase (Division phase)

Gap phase

•G1 devoted for metabolic activity for cell growth and preparation for DNA replication

•G2 preparation for mitotic cell division takes place

Check Point

Check Point

Checks DNA damageBefore final commitment for replication:

defect can be repaired as chromatids are still together

G1 arrest

Checks integrity of DNA Check completion of DNA replication.

Are they ready for mitosisG2 arrest

Cell Cycle check points

Control of the Cell Cycle

• Cdks (Cyclin-dependent kinases)

• Cyclins

• CKIs(Cyclin dependent kinase inhibitor )

The passage of a cell through the cell cycle is controlled by proteins in the cytoplasm. These protein are:

Complete regulation of cell cycle

CDK ( Cyclin dependent kinase) &Cyclins • CDK contain two parts, an enzyme

(kinase) and a modifying protein (Cyclin)

• Kinases are regulatory enzymes that catalyze the addition of phosphate groups to protein substrates

• Cyclins synthesize and degenerate at each cycle, work as docking site for substrate

• Cdk4 and Cdk6 regulate entry into cell cycle

• Cdk1 and Cdk2 operate primarily in M phase and S phase

CDK ( Cyclin dependent kinase) &Cyclins • CDKI have capability of sensing problems

• Kip family: P21waf1/cip1, P27kip1 ,P57kip2

• Ink4 family: P16Ink4a,P15Ink4b,P18Ink4c,P19Ink4d

• INK4 proteins binds to CDK 4 & 6

• Cip –Kip proteins binds to CDK 1 & 2

Cyclins and CDKs

Kinasecomplex

Vertebrate Yeast

Cyclin CDK Cyclin CDK

G1-CDK Cyclin D* CDK4 、 6 Cln 3 CDK1(CDC28)

G1/S-CDK Cyclin E CDK2 Cln 1、2

CDK1(CDC28)

S-CDK Cyclin A CDK2 Clb 5、6

CDK1(CDC28)

M-CDK Cyclin B CDK1(CDC2)

Clb 1-4 CDK1(CDC28)

Complete regulation of cell cycle

Tumor as result

• Overexpression of cyclins

• Overexpression of Cdks

• Deactivation of CkIs

• Abnormity of checkpoints

Normal cell

Inactivation of tumor suppressor gene

DNA damage

Activation of proto-oncogene

Unregulated proliferation Decreased apoptosis

Mutation in somatic cells

Alteration of apoptosis gene

Failure of DNA Repair

Tumor progression

Malignant neoplasm

Clonal expansion

Invasion Metastasis

Acquired DNA damaging agent

i.e. chemical, radiation, virus mutation i.e. genes

affecting DNA repair and apoptosis

pathway

Successful DNA repair

•Angiogenesis•Escape from immunity Additional mutation

Signs for Genomic Changes in Cancer• Changes in chromosome numbers

• Aneuploidy

• Chromosomal changes- Increase in DNA copy number - Loss in chromosome

• Hypermethylation at promoter region is a common mechanism by which tumor suppressor loci are epigenetically silenced in cancer cells (aberrant gene transcription)

LOH (Loss of heterozygosity)

Rb RbRb

Second hitInherited Rb

A

b

a

B

A

b

Pre-tumor cellTumor cell

• LOH termed as pre-tumor cells are heterozygous for tumor suppressor gene, alleles of genetic marker surround the gene

•Tumor cell will loss the normal tumor suppressor allele & surrounding markers too

Telomere and telomerase•TelomerTelomer 6 nucleotide sequence at end of chromosome to avoid the chromosomal end to end fusion

•Telomerase (RNA containing enzyme) Facilitate replication of telomer

•Mitotic clockNormally telomer loss at each cell division, serve as cellular mitotic clock to limit no. of cell division and cellular life span

•Cellular crisisIn extended cell division, loss of capping resulting into chromosomal instability which leads to loss of cell viability and proliferation capacity

Telomerase activity is detected in 80% to 90% most common cancer

What are the genes responsible for tumorigeniccell growth?Normal

Cancer

Proto-oncogenes Cell growthand

proliferationTumor suppressor genes

+

-Mutated or “activated”

oncogenes Malignanttransformation

Loss or mutation ofTumor suppressor genes

++

List of proto-Oncogene

List of tumor suppressor gene

Mutation leads to Oncogene

Each proto-oncogene is composed of 2 region: • Structural region (SR) encodes AA• Regulatory region (RR) modulate expression as per stimuli

Change in either SR or RR create active onco-gene

Regulatory region leads to inappropriate level of growth inducing protein

Structural mutation leads change in structure & function of protein

Proto-oncogene

oncogene

Ras is GTP binding protein act as digital switch

Ras regulate cell growth – Play a role in mitogenesis by 2

mechanism

• Nucleotide exchange (GDP by GTP)

• GTP hydrolysis ( convert active Ras to inactive Ras)

Mutated Ras:

Trapped in permanently active state due to loss of GTP hydrolysis through GAP binding

• Leads to continuous activation of MAP kinase signaling

p53 maintain integrity of Genome• P53 mutation is common in >50% human cancer

• Normal p53 maintain the genomic integrity via• Response to DNA damage (cell cycle arrest) via P21 CDK

inhibitor

• Inducing apoptosis

• Disruption/deletion of p53 gene • Uncorrected DNA damage• Uncontrolled cell proliferation via decreased apoptosis

Loss of normal Apoptosis pathway

• Inactivation of p53, leads increase in BCl-2: causes enhanced cell survival and genetic instability and clonal suspension and diversification of tumor without activation of death pathway

Normal cell

Inactivation of tumor suppressor gene

DNA damage

Activation of proto-oncogene

Unregulated proliferation Decreased apoptosis

Mutation in somatic cells

Alteration of apoptosis gene

Failure of DNA Repair

Tumor progression

Malignant neoplasm

Clonal expansion

Invasion Metastasis

Acquired DNA damaging agent

i.e. chemical, radiation, virus mutation i.e. genes

affecting DNA repair and apoptosis

pathway

Successful DNA repair

•Angiogenesis•Escape from immunity Additional mutation

Invasion and Metastasis

• Abnormal cells proliferate and spread (metastasize) to other parts of the body

• Invasion - direct migration and penetration into neighboring tissues

• Metastasis - cancer cells penetrate into lymphatic system and blood vessels

Cell migration via cell –cell intraction

•Majority of cancer occur in epithelial cells, normally maintenance of cell- cell contact maintained by (TJ & AJ) Junction, which maintains by cadherin

•Any disruption to cadherin to catenin results in loss of cell adhesion(Cadherin, integrins, Immunoglobulin and CD-44)

•E-cadherin also considered as metastatic suppressor

Cell- ECM (Extra cellular matrix) interaction

ECM provides not only scaffolding for the cellular constituents & also initiates tissue morphogenesis, differentiation and homeostasis

The ECM is composed of two main classesMacromolecules: ProteoglycansFibrous proteins i.e collagens, elastins, fibronectins and laminins

Cell –ECM interaction mediated by integrins receptor present on tumor cell

Loss of cadherin •Reduces the cells to adhere each other •Facilitate cell detachment from tumor•Advancing into surrounding tissue

Attached to the ECM component•Laminin of ECM bind to integrins of tumor• Activate the protease of tumor cell (MMPs)•MMPs degrades the iv collagen and release

VEGF as angiogenic stimuli

•MMP release activate the GF (PDGF, TGF) of ECM affect the growth of tumor•Degradation of ECM creates the passage of invasion & signal for angiogenesis

Tumor progression

Angiogenesis is a normal and necessary process

Angiogenesis is pivotal in:-

•Tissue growth and development

•Plays role in normal physiology

•Wound healing,

•Female reproductive cycle

•Inflammation and embryogenesis

Angiogenesis-Pathological Disorders

VEGF helps in the formation of new blood vessels that support tumor growth.

Function of Angiogenic factors

Recruitment of pericytes and smooth muscle cell

Blood vessel formation

FGF

Tie 2Blood vessel Stablization

and remodeling

Artery , vein differentiation, vessel remodeling

Epherins

Angiogenesis controls tumor growth.

• Tumor can stay in a ‘dormant’ state for long periods.

• The angiogenic switch allows for growth of the tumor to occur.

• Increased angiogenesis correlates with worse prognosis.

Angiogenic Switch dynamic balance of pro & anti-angiogenic factor tripped in favor of blood vessel formation

Link b/w Inflammation & Malignancy

Chronic inflammation leads to cancer

• H. Pylori Stomach cancer

• Chronic reflux esophagitis Barrett syndrome

• Chronic pancreatitis Ca Pancreas

• Ulcerative colitis Colon cancer

• HCV, HBV Liver cancer (HCC)

The most common cancer arise in the skin, prostate, breast, lung and colon

• More than 100 kinds of cancer• Most common type is skin cancer• Liver cancer• Stomach cancer• Prostate cancer• Colon, breast, and lung

Grading and staging

• Grade: GX: Grade cannot be assessed

(Undetermined grade)

G1 Well-differentiated (Low grade)

G2 Moderately differentiated (Intermediate grade)

G3 Poorly differentiated (High grade)

G4 Undifferentiated (High grade)

• Staging systems (various): carcinoma

– Stage 1: confined to organ– Stage 2: locally invasive– Stage 3: lymph node invasion– Stage 4: spread to distant sites

Extent of the prim. tumor and extent of spread in the body

Helps planning treatment and Prognosis

TNM - system

• Most common (accepted by UICC, AICC)

• Based on : T extent of the tumor

N extent of spread to the lymph nodes

M presence of metastasis

• Number indicates size or extent of the prim. tumor and the extent of spread of metastasis

Cancer Treatment and Prevention

When a person is diagnosed with cancer, a variety of weapons are available to combat it

1-local therapy:• Surgery.• Radiation therapy

2-systemic treatment:• chemotherapy.• Hormonal therapy• Monoclonal antibodies• Radioactive material

Detection method of Cancer

• Amplification Technique

• Sequencing

• Microarray

• Protein array

• Tissue microarray Visualization

• Tissue microarray analysis

Summary

• Defect in cell division

• Mutation

• Invasion , metastasis & Angiogenesis

Benign Tumor

MalignantTumor