Molecular basis of multi-step carcinogenesis

1. General

   1. No singe oncogene can fully transform cells in vitro

      1. However, ras and myc together can transform fibroblasts

   2. Every human cancer reveals multiple genetic alterations

   3. Temporal sequence determine propensity of tumor development

   4. Concept of gatekeeper and caretaker genes

      1. examples of gatekeeper: APC/NF-1

      2. examples of caretakers: BRC-2

      3. higher risk of cancer in pts with defective gatekeeper genes

         1. only need “one hit” to develop cancer

2. Initiation/promotion theory: two stages of tumor development

   1. Tumor initiation

      1. exposure to carcinogen

      2. alters cell so it is more likely to give rise to a tumor

      3. for initiation to occur, CELL MUST DIVIDE AT LEAST ONCE

         1. makes the mutation permanent, fixed in DNA

   2. Tumor promotion

      1. promoters cause cancer in initiated cells but not by themselves

      2. they are reversible—don’t effect DNA directly

      3. examples

         1. phorbol esters

         2. hormones/drugs

      4. causes cell proliferation of initiated cells

      5. following proliferation, may develop more mutations and then tumor develops

Category: Pathology Notes