Carcinogenesis Stages & Mechanisms

Eva Szabo & Gail L. Shaw

Epigenetic Mechanisms of Chemical Carcinogenesis James E. Klaunig, Lisa M. Kamendulis, and Yong Xu Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine

Clinical relevance: There is mounting evidence that cellular senescence acts as a "cancer brake" because it takes many divisions to accumulate all the changes needed to become a cancer cell. In addition to the accumulation of several mutations in oncogenes and tumor suppressor genes, almost all cancer cells are immortal and, thus, have overcome the normal cellular signals that prevent continued division. Young normal cells can divide many times, but these cells are not cancer cells since they have not accumulated all the other changes needed to make a cell malignant. In most instances a cell becomes senescent before it can become a cancer cell. Therefore, aging and cancer are two ends of the same spectrum. The key issue is to find out how to make our cancer cells mortal and our healthy cells immortal, or at least longer-lasting. Inhibition of telomerase in cancer cells may be a viable target for anti-cancer therapeutics while expression of telomerase in normal cells may have important biopharmaceutical and medical applications. In summary, telomerase is both an important target for cancer and for the treatment of age-related disease.

Breast Cancer Continuum: intervention possibilities Prevention of Clinically Detectable Breast Cancer Pre- Malignant Conditions LCIS 6.5% ADH 5.1% Women at Increased Risk 1.7 % to 14% Non- Invasive Cancer DCIS 7.2% Prevention of Contralateral Breast Cancer 3.2% Tumors < 1cm 11.8% Early Stage node neg 25.1% Early Stage node pos 47.1% Prevention of Recurrence Late Stage Cancer Recurrence of Breast Cancer Prevention of Progression

With thanks to Professor W.Jonat Breast Cancer staging

With thanks to Professor W.Jonat Breast Cancer staging 2

With thanks to Professor W.Jonat Breast Cancer staging 3

Stages of tumour development Malignant cell Dissemination of other organs Invasion Proliferation Angiogenesis Neovascular endothelial maintenance Invasion Cytotoxics Endocrine EGFR inhibitors HER2 antibodies Anti- angiogenics Vascular targeting agents Novel agents Metastatic Cancer of other organs

Staging Classification of Breast Tumour

OVEREXPRESSION OF p68 RNA HELICASE IN COLORECTAL TUMORS We and others have shown that p68 RNA helicase is overexpressed in colon cancer. In particular, hyperplastic polyps which eventually develop via adenomas into malignant adenocarcinomas, are devoid of significant p68 RNA helicase immunostaining (see Figure). However, adenomas as well as adenocarcinomas show p68 RNA helicase overexpression, suggesting that p68 RNA helicase may contribute to the malignant transformation of colon cells. Janknecht LaboratoryJanknecht Laboratory, Mayo Clinic