Carcinogenesis

Carcinogenesis

1. Carcinogenesis Mohammed Fathy Bayomy, MSc, MD Lecturer Clinical Oncology & Nuclear Medicine Faculty of Medicine Zagazig University

2. Multistep Carcinogenesis

3. Stages 1) Initiation * Caused by mutation following application of initiating agent * Once mutation is fixed by mitosis, it is irreversible * Cells histologically appear normal inspite of genetic damage * Initiated cells are also diploid, with normal DNA content * Initiator - Chemical e.g. smoking & alcohol) or - Radiation (e.g. solar ultraviolet irradiation)

4. 2) Promotion * Characterized by cell proliferation (clonal expansion), & reversible after cassation of promoting agent * Promoting agents act through increase in growth factor which stimulate cell proliferation through epigenetic mechanism * Histologically, pre-neoplastic lesion in form of dysplasia or benign tumor * Promoted cells are usually diploid

5. * Promotor - Experimental (croton oil ‘‘phorbol ester’’ saccharine, plastic) - Human promoting agents (bile acids, hormones, oncogenic viruses growth factors)

6. 3) Progression * Results from multiple, mutations in proliferating cellular subclones which results in intratumor molecular heterogeneity * Irreversible process * Histologically: cellular anaplasia, other malignant biological feature, cells are aneuploid

7. Initiation Promotion Progression Sequence First Second Third Biology Mutation Clonal expansion Clonal evolution Ploidy Diploid Diploid Aneuploid Reversibility Irreversible Reversible Irreversible Histology Unremarkable Precancerous lesion Malignant tumor

8. Multihit Carcinogenesis Proposed by: Vogelstein after extensive genetic & pathologic studies on adenoma carcinoma sequence in colon State * Cancer develops as result of accumulation of multiple genetic lesions involving activation of proto-oncogenes & loss of tumor suppressor genes * Mutation of at least 4 to 5 genes are necessary for formation of truly malignant tumor * Total accumulation of genetic lesions, rather than their order of sequence, which is most critical in cancer development (multihit rather than multistep process)

9. Monoclonality of Cancer Cancer arises through multistep accumulation of somatic gene mutations in progeny of single cell of origin (monoclonal) Accumulation of mutations in different subclones will ultimately lead to molecular intratumour heterogeneity Tumour cell subclones, compete with each other on basis of growth rate, with ultimate survival & predominance of more aggressive subclones (clonal evolution) Two driving forces of malignancy are mutagenesis & mitogenesis

10. Monoclonal, or single cell, origin of cancer is supported by two, histochemical observations in malignant tumours: * G6PD isoenzyme: normal cells contain two isoenzymes (A & B) of enzyme glucose 6-phDsphate dehydrogenase (G6PD). Whereas, malignant tumours which arise from these normal tissue contain only one, isoenzyme, either A, or B, hence confirming monoclonal origin of tumor * Light chain restriction: normal B lymphocytes carry on their surface immunoglobulin with two types of light chain