Types of Cancer

1. CancerDevelopment and Causes of CancerTumor VirusesOncogenes/Tumor Suppressor GenesMolecular Approaches to Cancer Treatment

2. Types of Cancer Cancer can result from abnormal proliferation of any of the different kinds of cells in the body, so there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment. A tumor is any abnormal proliferation of cells, which may be either benign or malignant.

3. Types of Cancer A benign tumor remains confined to its original location, neither invading surrounding normal tissue nor spreading to distant body sites. A malignant tumor is capable of both invading surrounding normal tissue and spreading throughout the body via the circulatory or lymphatic systems. Metastasis is the spread of cancer cells through the blood or lymphatic system to other organ sites. Carcinomas are malignancies of epithelial cells. Sarcomas are solid tumors of connective tissues, such as muscle, bone, cartilage, and fibrous tissue.

4. Types of Cancer Leukemia is a cancer arising from the precursors of circulating blood cells. Lymphomas arise from the cells of the immune system. Although there are many kinds of cancer, only a few occur frequently.

5. The Development of Cancer One of the fundamental features of cancer is tumor clonality—the development of tumors from single cells that begin to proliferate abnormally. The clonal origin of tumors does not imply that the original progenitor cell that gives rise to a tumor has initially acquired all of the characteristics of a cancer cell.

6. The Development of Cancer • At the cellular level, the development of cancer is viewed as a multistep process involving mutation and selection for cells with progressively increasing capacity for proliferation, survival, invasion, and metastasis. • Tumor initiation is thought to be the result of a genetic alteration leading to abnormal proliferation of a single cell.

7. The Development of Cancer Tumor progression continues as additional mutations occur within cells of the tumor population. Studies of colon carcinomas have provided a clear example of tumor progression during the development of a common human malignancy. An adenoma (or polyp) is a small benign neoplasm arising from the glandular epithelium.

8. 18.5 Development of colon carcinomas • Studies of colon carcinomas have provided a clear example of tumor progression during the development of a common human malignancy.

9. Causes of Cancer Carcinogens, substances that cause cancer, have been identified both by studies in experimental animals and by epidemiological analysis of cancer frequencies in human populations. Radiation and many chemical carcinogens act by damaging DNA and inducing mutations. Tumor promoters contribute to cancer development by stimulating cell proliferation, rather than by inducing mutations.

10. Properties of Cancer Cells The uncontrolled growth of cancer cells results from accumulated abnormalities affecting many cell regulatory mechanisms. Density-dependent inhibition is the cessation of the proliferation of normal cells in culture at a finite cell density.

11. Properties of Cancer Cells The growth factor requirements of many tumor cells are reduced compared to their normal counterparts, contributing to the unregulated proliferation of tumor cells both in vitro and in vivo. Autocrine growth stimulation is stimulation of cell proliferation as a result of growth factor production by a responsive cell.

12. 18.9 Contact inhibition • Contact inhibition is the process in which normal fibroblasts migrate across the surface of a culture dish until they make contact with a neighboring cell.

13. Properties of Cancer Cells • Angiogenesis is the formation of new blood vessels and is needed to support the growth of a tumor beyond the size of about a million cells, at which point new blood vessels are required to supply oxygen and nutrients to the proliferating tumor cells. • The leukemias provide a particularly good example of the relationship between defective differentiation and malignancy. • Programmed cell death, or apoptosis, is a normal physiological form of cell death.

14. Transformation of Cells in Culture Cell transformation is the conversion of normal cells to tumor cells in culture. The first and most widely used assay of cell transformation is the focus assay.

15. Tumor Viruses • Tumor viruses are capable of directly causing cancer in either experimental animals or humans. • Tumor viruses not only are important as causes of human disease but have also played a critical role in cancer research by serving as models for cellular and molecular studies of cell transformation.

16. Papillomaviruses Papillomaviruses are small DNA viruses that induce both benign and malignant tumors in humans and a variety of other animal species. Cell transformation by human papillomaviruses results from expression of two early-region genes, E6 and E7.

17. Retroviruses Retroviruses cause cancer in a variety of animal species, including humans. Different retroviruses differ substantially in their oncogenic potential. Rous sarcoma virus, or RSV, contains specific genes responsible for induction of cell transformation and is a potent carcinogen.

18. Oncogenes Oncogenes are specific genes that are capable of inducing cell transformation. The majority of human cancers are not induced by viruses and apparently arise from other causes, such as radiation and chemical carcinogens.

20. Proto-Oncogenes An unexpected feature of retroviral oncogenes is their lack of involvement in virus replication. The first clue to the origin of oncogenes came from the way in which the highly oncogenic retroviruses were isolated.

21. Proto-Oncogenes Proto-oncogenes are normal cell genes that can be converted into oncogenes. Oncogenes frequently encode proteins that differ in structure and function from those encoded by their normal homologs.

22. Oncogenes in Human Cancer Direct evidence for the involvement of cellular oncogenes in human tumors was first obtained by gene transfer experiments. Ras oncogenes are not present in normal cells; rather, they are generated in tumor cells as a consequence of mutations that occur during tumor development.

23. Oncogenes in Human Cancer c-myc is a proto-oncogene that encodes a transcription factor and is frequently activated by chromosome translocation or gene amplification in human tumors.

24. Oncogenes in Human Cancer The abl proto-oncogene encodes a protein-tyrosine kinase and is activated by chromosome translocation in chronic myeloid leukemia. The N-myc proto-oncogene encodes a transcription factor and is frequently activated by amplification in neuroblastomas. The erbB-2 proto-oncogene encodes a receptor protein-tyrosine kinase that is frequently amplified in breast and ovarian carcinomas. Ras is a Frequently mutated Proto-oncogene.

25. Functions of Oncogene Products The function of oncogene proteins in regulation of cell proliferation is illustrated by their activities in growth factor-stimulated pathways of signal transduction. A large group of oncogenes encode growth factor receptors, most of which are protein-tyrosine kinases.

26. Functions of Oncogene Products The failure of cancer cells to undergo programmed cell death is a critical factor in tumor development. PI 3-kinase and Akt act as oncogenes in both retroviruses and human tumors. Bcl-2 is a member of a family of proteins that regulate programmed cell death.

27. Identification of Tumor Suppressor Genes Tumor suppressor genes act to inhibit cell proliferation and tumor development. In the first insight into the activity of tumor suppressor genes, the fusion of normal cells with tumor cells yielded hybrid cells containing chromosomes from both parents. The first tumor suppressor gene was identified by studies of retinoblastoma, a rare childhood eye tumor.

28. Identification of Tumor Suppressor Genes Rb, a tumor suppressor gene, is present on homologous chromosomes of a normal diploid cell. The functional nature of the Rb gene as a negative regulator of tumorigenesis was initially indicated by observations of chromosome morphology.

29. 18.34 Rb deletions in retinoblastoma

30. Identification of Tumor Suppressor Genes Although Rb was identified in a rare childhood cancer, it is also involved in more common tumors of adults. Characterization of Rb as a tumor suppressor gene served as the prototype for the identification of additional tumor suppressor genes.

31. Functions of Tumor Suppressor Gene Products The PTEN tumor suppressor gene is an interesting example of antagonism between oncogene and tumor suppressor gene products. The products of the Rb and INK4 tumor suppressor genes regulate cell cycle progression at the same point as that affected by cyclin D1 and Cdk4, both of which can act as oncogenes.

32. Functions of Tumor Suppressor Gene Products The p53 gene product regulates both cell cycle progression and apoptosis. Stability genes act to maintain the integrity of the genome.

33. Roles of Oncogenes and Tumor Suppressor Genes in Tumor Development The role of multiple genetic defects is best understood in the case of colon carcinomas, which frequently involve mutations of oncogenes or tumor suppressor genes. Accumulated damage to multiple oncogenes and tumor suppressor genes, affecting distinct pathways that regulate cell proliferation and survival appear to be responsible for the multistage development of colon cancer.

34. Prevention and Early Detection The most effective way to deal with cancer would be to prevent development of the disease. The reliable identification of susceptible individuals, if it were followed by appropriate preventive and early detection measures, might ultimately make a significant impact on cancer mortality.

35. Molecular Diagnosis Molecular analysis of the oncogenes and tumor suppressor genes involved in particular types of tumors has the potential of providing information that is useful in the diagnosis of cancer and in monitoring the effects of treatment. The detection of mutations in specific oncogenes or tumor suppressor genes may provide information pertinent to choosing between different therapeutic options. The most critical question is whether the discovery of oncogenes and tumor suppressor genes will allow the development of new drugs that act selectively against cancer cells.

36. Treatment One promising new approach to cancer therapy is the use of drugs that inhibit tumor growth by interfering with angiogenesis or disrupting tumor blood vessels, rather than acting directly against cancer cells. An alternative strategy for achieving more selective cancer treatment is the development of drugs targeted specifically against the oncogenes that drive tumor growth.

37. 18.41 EGF receptor mutations associated with sensitivity to gefitinib • A small molecule inhibitor of the EGF receptor has recently shown striking activity against a subset of lung cancers in which the EGF receptor is activated by point mutations. • Oncogene addiction is the sensitivity of tumors to inhibition of activated oncogenes.