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

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 system cells, 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

Cell cycle (Cancer) Cyclin-dependent kinases inhibitors (CDKI): –Kip/Clip: p21, p27, p57 –INK: p15, p16, p18, p19 + CDK4 or CDK6 cyclin Cyclin- dependent kinases TGF-beta, p53 (tumor suppressor genes)  CDKI  CDK

pRB E2F P TS NORMAL CELL CYCLE Inactivation of Rb in tumors: retinoblastoma small-cell lung cancer soft tissue sarcoma glioblastoma breast cancer bladder carcinoma

Positive regulators of G1 phase progressions CDK-CYCLIN COMPLEXES CDK-ACTIVATING KINASE

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

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

Negative regulators of G1 phase progressions

CYCLIN-DEPENDENT KINASE INHIBITORS p21 cip1 CIP/KIPp27 kip1 p57 kip2 p16 INK4a p15 INK4b INK4p18 INK4c p19 INK4d

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

Cip/Kip CDKI p21= waf1=Sdi1 inhibits cyclin/CDK function through cell cycle p27kip1 bound to cyclin/CDK4;

Cell cycle gene alternations in canaer pRb deletion / mutation p16 deletion / mutation p27 inactivation (methylation) cyclin D1 overexpression cyclin E overexpression CDK4 overexpression

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

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: , with permission.

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: , with permission.

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.