Chapter 16- Cancer

1. Chapter 16- Cancer Where we’re going • Characteristics of cancer cells • Some names • Convince you that cancer is a result of multiple genetic defects • Molecular genetics of cancer • We’ll be connecting cancer to growth and signaling. • A few treatments

2. Why this is important • About 1 in 4 of us get cancer, 1 in 5 die of it- at least. • It’s very much a disease that can be understood at the molecular level. • Our understanding has not resulted in the cures we’d like

3. No particular relevance- painted by Van Gogh in the 1880’s!

4. Cancers vary in terms of getting a type of cancer and dying from that type Data 2000-2003

5. Basic Properties of cancer cells • Uncontrolled- grow at the usual rate, but then keep growing when other cells would normally stop- ignore stopping signals, or grow w/o added signals. • Invasive • Immortal- normal cells undergo senescence- telomerase is 1 factor. • Chromosomal abnormalities- aneuploid

6. Well-behaved- stop growing when they cover the dish.

8. Not well-behaved- keep growing after they cover the dish.

10. Internal signals allow serum-free growth

12. Names: • A. tumor/neoplasm: clone of cells capable of uncontrolled growth; • benign: contained • malignant: spreading • B. classified by tissue of origin: • carcinoma-epithelial tissue • sarcoma- mesodermal origin: muscles, connective tissue, vascular tissue • leukemia/lymphoma- blood forming (hemopoietic) cells

13. Origins of cancer cells • Clonal, but highly mutable • Chronic myelogenous leukemia-translocation from 22 to 9 (Philadelphia chromosome)

14. More than one defect: • 1016 cell divisions in a lifetime; • even at a mutation rate of 1/106, we'd have 1010 mutations in every gene! Thus, it may take 3--7 events, in the same cell, to make it cancerous. evidence:

15. 1. frequency of cancer, peryear, goes up with age- accumulated mutations. Molecular evidence agrees with this. • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4270 Colon cancer of women in England & Wales

16. 2. tumor progression: e.g., cervical carcinoma: the cells can be in a precancerous stage; undifferentiated; some may be immortal; yet not be cancerous. Only a fraction of the precancerous cells become cancerous. Thus, the changes are typically sequential, rather than having to be simultaneous. Very much an evolutionary event!

17. Normal- small nuclei

18. Precancerous- carcinoma in situ

19. The initiator is mutagenic, while the promoter stimulates growth- the mutant population increases, increasing the likelihood of further mutations • 3. Initiator/promoter studies: Fig. 23-19, MBOC: • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4300 • Many cells revert to a less differentiated stage- carcinoembryonic antigen is expressed in embryos, and also in cancers.

20. 4. Molecular evidence: With the advent of cloned oncogenes, it's been possible to add such genes to normal cells or animals, and determine the results. a. 3T3 cells- already abnormal; single added oncogene makes them cancerous. b. normal cells require two oncogenes: myc & ras both result in transformation. Same results with transgenic mice. 23-30 http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4325 These are mice with transgenic, overexpressed oncogenes.

21. A typical progression of cancer

26. So what causes all those mutations? • Life • Maybe mutagens • Viruses in some cases • Diet can have an effect

28. However, correlation doesn’t necessarily mean causation…

29. How are cancer cells different in gene expression? • We can use microarrays to find out! • 1000’s of gene-specific sequences. • Isolate mRNA from cell, turn into cDNA • Hybridize to sequences • Can quantify amounts.

30. ALL- lymphoid- lymphocytes AML: myeloid- granulocytes, macrophages, dendritic cells

33. Sometimes this helps- or not

35. IV. Molecular genetics of cancer: Two basic effects that genes can have on cell growth; • A. stimulate growth: oncogenes; genes that are normally turned on as part of growth, now unusually active. Dominant mutations; also DNA tumor virus genes. • B. inhibit excessive growth: some genes seem to be there to keep oncogenes in line; these mutations tend to be recessive. Tumor suppressor genes, • Cell fusion studies can differentiate between these- Suppressors are recessive to normal, and oncogenes are often dominant over normal.

36. C. types of stimulatory genes: • 1. DNA tumor virus genes: non-permissive infections result in excessive growth: human viruses infecting hamsters. The virus produces a protein that, in one case binds and inactivates two of the major tumor suppressor genes- Rb and p53, thus allowing uncontrolled DNA replication. (Fig 23-35) • http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4334

37. Oncogenes: most were discovered in RNA tumor viruses: carried by certain tumor viruses. We have homologous genes- proto-oncogenes. Types- Cell signaling (RAS), cell regulating, growth factors, GF receptors, transcription factors, anti-apoptosis proteins.

39. With more changes…

40. Ways to become a bad oncogene

41. New copy, overexpressed, comes in from retrovirus! Retrovirus activates, by insertion, nearby proto-oncogene!

43. These are all oncogenes

44. Tumor suppressor genes • Tend to halt unregulated cell growth-cell cycle control w/ damage, or inappropriate signals. • Need TWO bad copies before problems occur- recessive.

45. With further mutations

46. Retinoblastoma gene- hereditary cancer w/ 90% penetration- born w/ 1 bad copy. It normally is stopping S phase. E2F is major TF, turns on many genes.

49. P53- the guardian of the genome!! • Transcription factor • Made but unstable • DNA damage (ATM-> CHK2->phosphorylated/stable) • P21 transcribed- binds CDK/Cyclin, stops G1-S transition. • Activates apoptotic genes as well