Colon cancer: the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development

Familial adenomatous polyposis (FAP) = inherited predisposition to colon cancer

Cancer cells proliferate without differentiating, a property of our body’s normal stem cells

Normal cells are “contact-inhibited” and stop growing when they reach confluence Tumor cells are no longer “contact inhibited”

Cancer cells have alterations in cell adhesion and the cytoskeleton Normal “Transformed”

Normal Dysplasia Carcinoma in situ Malignant carcinoma Cancer develops through gradual changes in cell morphology and properties

Benign tumor Break through basal lamina Invade capillary Adhere to capillary wall Escape capillary Form metastasis Metastasis: the movement of tumor cells to new sites via the blood vessels or lymphatic system

Some normal cells like those of the neural crest have similar properties but end by differentiating at their new sites

The forces of Natural Selection drive the multistep process ECB Fig

A single mutation is NOT enough!

Cancer cells accumulate chromosomal abnormalities

What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation

What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation Tumor suppressor genes Mutational inactivation of proteins that normally inhibit cell proliferation

Cells instruct one another via cell-cell signals

Signal transduction moves information from the cell surface to the nucleus & other cellular targets

Signal transduction occurs in a series of steps

Cell-cell signals can regulate cell proliferation

Cancer often results from alterations in proteins in signal transduction pathways

Cancer often results from alterations in proteins in signal transduction pathways

Src in its normal context Normal skin cell tightly adherent to ECM Wounding->platelet recruitment-> cell migration and proliferation

Many viral oncogenes are kinases including receptor tyrosine kinases

Activating mutations in RTKs take several forms but all lead to ligand-independent dimerization and thus activation

Double minute chromosomes Tandem duplications Gene amplification is also a common mechanism of inappropriate gene activation in human tumors

RTK signaling ultimately leads to activation of a transcription factor Gilbert Fig. 6.15

Elements of the ras signal transduction pathway are often activated in cancers

Remember this?

The vul mutations helped define the RTK-Ras pathway

We are making progress: The modern drug Gleevec stops certain cancers by blocking the kinase activity of protein tyrosine kinases Gleevec works for chronic myeloid leukemia

Lipid bilayer Outside the cell Inside the cell Steel White-spotting Tyrosine kinase domain In response to binding of Steel factor, kinase is activated and target proteins are phosphorylated P (aka c-kit) Gleevec also works for the cancers caused by activation of White-spotting=(c-kit)

What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation Tumor suppressor genes Mutational inactivation of proteins that normally inhibit cell proliferation

E2F DP DO NOT transcribe gene required for DNA replication Rb Rb puts the brakes on cell proliferation

E2F DP Transcribe gene required for DNA replication P P Rb phosphorylation frees E2F/DP to turn on genes required for proliferation

Retinal tumor in patient that inherited a mutant copy of Rb

Even though its caused by a loss-of-function mutation Retinoblastoma is inherited in a dominant fashion What’s up with that?

Mechanisms to inactivate the second Rb allele

One strategy for isolating oncogenes