benign tumor: abnormal proliferation of cells that remain contained and don’t spread to other...

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Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable of spreading to surrounding Tissues and invading body organs via the circulatory and/or the Lymphatic systems (metastasis). Only these are called cancers. Types of cancer

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Page 1: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart)

Malignant tumor: cells are capable of spreading to surrounding Tissues and invading body organs via the circulatory and/or theLymphatic systems (metastasis). Only these are called cancers.

Types of cancer

Page 2: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Carcinomas: epithelial cells, 90% of all cancers

Sarcomas: connective tissues as muscle, bone, etc. Rare in humans.

Leukemias and lymphomas: blood forming cells and immune systemcells, respectively. ~8%.

Tumors are also classified by the tissue of origin (breast, lung, colon)

Tumors are classified according to the type of cell from which they arise

Page 3: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable
Page 4: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Cell cycle (Cancer)

• Cyclin-dependent kinases inhibitors (CDKI):– Kip/Clip: p21, p27, p57– INK: p15, p16, p18, p19 + CDK4 or CDK6 cy

clin

• Cyclin- dependent kinases

• TGF-beta, p53 (tumor suppressor genes) CDKI CDK

Page 5: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

pRB pRBE2F

E2F

P

TS

NORMAL CELL CYCLE

Inactivation of Rb in tumors:

retinoblastomasmall-cell lung cancersoft tissue sarcomaglioblastomabreast cancerbladder carcinoma

Page 6: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Positive regulators of G1 phase progressions

CDK-CYCLIN COMPLEXES

CDK-ACTIVATING KINASE

Page 7: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

CYCLIN D

• 3 Cyclin D genes

• synthesised by mid-G1 phase and maximum at G1/S boundary

• stimulated by growth factors

• promote catalytic activity of CDK4 and CDK6

Page 8: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

CYCLIN E

• synthesis at late G1 phase

• complexes with CDK2

• ectopic overproduction contracts G1, reduces cell size and decreases cellular dependency on mitogenic growth factors

Page 9: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Negative regulators of G1 phase progressions

Page 10: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

CYCLIN-DEPENDENT KINASE INHIBITORS

p21cip1

CIP/KIP p27kip1

p57kip2

p16INK4a

p15INK4b

INK4 p18INK4c

p19INK4d

Page 11: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

INK4 CDKI

• specifically target CDK’s

• INK4 proteins sequester cdk4/6 into complexes liberating cip/kip proteins

• ability to arrest in G1 dependent on intact pRb

Page 12: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Cip/Kip CDKI

• p21= waf1=Sdi1 inhibits cyclin/CDK function through cell cycle

• p27kip1 bound to cyclin/CDK4;

Page 13: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Cell cycle gene alternations in canaer

• pRb deletion / mutation

• p16 deletion / mutation

• p27 inactivation (methylation)

• cyclin D1 overexpression

• cyclin E overexpression

• CDK4 overexpression

Page 14: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

They normally inhibit cell proliferation and tumor development.In many tumors, these genes are lost or inactivated.

Ex. Retinoblastoma gene (Rb) p53 BRCA1 and 2 APC (familial colon cancer)

Tumor Suppressor Genes

Page 15: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable
Page 16: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Cell Cycle Regulation

The cell cycle is regulated by cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDKIs) and is divided into 4 distinct phases (G1, S, G2, and M). G0 represents exit from the cell cycle. The cell cycle is driven by CDKs, which are positively and negatively regulated by cyclins and CDKIs, respectively. The restriction point governs the transition point beyond which progression through the cell cycle is independent of external stimuli.

Adapted from Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

Page 17: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Rb and the G1-S Transition

Retinoblastoma gene product (Rb) governs entry into S phase. Hypophosphorylated Rb forms a complex with a group of transcription factors, E2F. When Rb is inactivated by CDK2-, CDK4-, or CDK6-mediated phosphorylation, E2F transcription factors are released, resulting in progression into S phase and transcription of a range of targets involved in chemotherapy sensitivity.

Adapted from Shah and Schwartz. Clin Cancer Res. 2001;7:2168-2181, with permission.

Page 18: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable

Cell Cycle Inhibition by Flavopiridol

Flavopiridol is a pan–cyclin-dependent kinase (CDK) inhibitor of CDK1 (Cdc2), CDK2, CDK4, and CDK6 at nanomolar concentrations, resulting in cell cycle arrest at both the G1/S and the G2/M transitions.

Page 19: Benign tumor: abnormal proliferation of cells that remain Contained and don’t spread to other tissues (ex. Skin wart) Malignant tumor: cells are capable