Molecular Basis of Cancers

q  uncontrolled cell division

q  genetic defect in signaling pathway, transcription factor, DNA repair

q  usually requires multiple mutations q  inherited or environmental

Transformation of Cultured Cells

Oncogenes

q  discovered in tumor causing viruses

q  derived from host genes – proto-oncogenes q  encode growth factors, receptors, signaling molecules, transcription factors q  genetically dominant – mutation of single gene sends “divide signal”

Amplification of Proto-oncogenes

ErbB Oncogene – Mutated EGF Receptor

Cancers of the - breast - stomach - ovaries

Effect of Multiple Oncogenes on Tumor formation in Mice

Tumor Suppressors

q  normally restrain cell growth

q  genetically recessive – require mutation of both genes

q  if inherit one mutant gene – greater risk

q  examples - pRB – retinoblastoma - p53 – >50% all cancers, 90% skin cancers

Function of Tumor Suppressors

Figure 20-30 Molecular Biology of the Cell (© Garland Science 2008)

Development of Retinoblastomas

DNA Repair Genes

Examples: - ATM – kinase that detects DNA damage, activates p53 - XP – xeroderma pigmentosum - BRCA1 – breast cancers

Colorectal Cancer

q  accounts for 10 % of all cancers in US (about 60,000 deaths/yr) - 90% age >55

q  epithelial cells turnover rapidly, derived from stem cells in crypt, migrate up villi, and sloughed into lumen

q  progression from early polyp (small, benign proliferation of stem cells) to metastatic cancer requires 10-12 years

Tumor Progression in Colon Cancer

Alternative Pathways to Colorectal Cancer