Tumor Radiation Biology

1. Tumor Radiation Biology

2. Tumor Radiation Biology • Tumors represent uncontrolled growth of a cell population. • Loss of contact inhibition – overpopulation • Disordered growth • Non-uniform phenotype (cell characteristics) Chaotic gene expression • Some cells in population hypoxic?

3. Tumor Induction • Mutations or changes in cellular population control mechanisms • Proto-oncogenes • Tumor suppressor genes • DNA stability genes

4. Proto-Oncogenes • Positive grow regulators • Promote cell division and decrease response to extracellular control signals • Requires only a single copy of the gene to result in up-regulation. • Blunts cell to cell contact growth inhibition.

5. Tumor Suppressor Genes • Negative growth regulators • Antagonists of proto-oncogenes • Decreases cell growth potential • Increase negative growth signals of cell to cell contact. • Inactivation of both copies of gene required to result in complete loss of function

6. DNA Stability Genes • Monitor and maintain the integrity of the DNA. • Loss of function promotes mutations • Detection of DNA lesions decreased • Repair of damage decreased or improper • Decreased apoptosis

7. Neoplastic Transformation • Tumor cells typically arise from a normal cell population. > • Mutation in growth control mechanism (often more than one) > • Abnormal cells begin to proliferate > • Cells escape detection by body’s immune system > • Invasion of surrounding tissue.

8. Mechanisms of Proto-oncogene Mutation or Expression • Retroviral integration • Retroviral genome integrates with DNA near oncogene and promotes activation • DNA mutation of regulatory sites • Mutation reduces regulatory activity by alteration of protein transcription • Can be alteration of a single base pair

9. Mechanisms of Proto-oncogene Mutation or Expression • Gene Amplification • Improper DNA replication leads to multiple copies of gene • Increased numbers of copies promotes up-regulation of oncogene. • Seen in leukemia, and breast cancer

10. Mechanisms of Proto-oncogene Mutation or Expression • Chromosomal translocation • Tumor Chromosomes different from normal cells. • Abnormal reproduction (mutation) results in part of one chromosome being removed and attached to another. • Recombination may promote oncogene expression. • Some recombinations occur repeatedly

11. Mechanisms of Proto-oncogene Mutation or Expression • Multiple mechanisms may be present in any given tumor genotype. • Modified or amplified by mutations in tumor suppressor gene activity • Must escape detection by DNA integrity monitoring and repair systems. • Clonogenic activity preserved

12. Inactivation of Tumor-Suppressor Genes • These genes provide control of oncogenes. • Recessive genes but still function • Loss of both copies of these genes is generally required to allow tumors to grow • The effect can be a sporatic mutation in and individual cell or in some cases is a heritable disorder.

13. Inactivation of Tumor-Suppressor Genes • Inactivate or lost through somatic homozygosity. • A mutation occurs in the gene on one chromosome. • The complimentary chromosome is loss through mitotic misadventure • The remaining chromosome self replicates • Daughter cell winds up with a self-copy of the mutated gene.

14. Cancer is a Multi-Step Process • DNA damage (radiation etc.) > • DNA damage multiplied • Both pro oncogenes and oncogene suppressors affected. • Usually multiple cellular systems affected. • Eventually an imortalized clonogenic cell develops and tumor growth begins

15. Cancer is a Multi-Step Process • Deregulation of cellular proliferation through suppression of many genes • Failure of cells to respond the growth restrictive signals • Failure of excess cells to undergo apoptosis. • Apoptosis is major effect of p53. • Escape from senescence • Cell aging does not occur.

16. Cancer is a Multi-Step Process • Angiogenesis – in order to grow a tumor must recruit and establish a blood supply. • Certain genes promote or inhibit endothelial cell growth • Mutation can cause down or up regulation • Invasion and metastasis occur • In metastasis cell adhesion is lost • Sign of a very deranged growth in a cell

17. Cancer is a Multi-Step Process • Lastly cancer cells must possess mechanisms to avoid replication arrest at the cell cycle checkpoints • G1- S p53 dependent • S phase arrest mediated by Cyclin A & E • G2 – M mediated multiple gene products

18. Cancer is a Multi-Step Process Radiation injury to the DNA may promote neoplastic transformation by either inhibiting or damaging genes which control cell growth and replication or by causing damage which promotes up regulation of genes which actively causes uncontrolled cell growth.

19. Tumor Radiation Biology • Tumor tissue exhibit chaotic growth and phenotype patterns • Cells in different areas of tumor may have different appearances • Different size • Different chromosomal imprints • Different cytoplasmic and nuclear patterns • Different adhesion characteristics • May be unrecognizable from parent cells or not look like them at all.

20. Tumor Radiation Biology • Stromal and other support cells are poorly developed or not at all. • Connective tissue lattice • NO nerve supply • Poorly developed vascular and lymphatic system. • Frequently large #’s of inflammatory cells due to dying non-viable cells

21. Tumor Radiation Biology • Hypoxia is a feature of tumors not found in normal tissues. • Tumor vascularity is primitive and growth is not controlled by genetic template. • Tumor vascularity tends to be primitive • Blood flow in tumors while copious is sluggish • Tumor volume not uniformly vascularized • Tumor cells may use oxygen inefficiently

22. Tumor Hypoxia • Four different subpopulations of tumor cells with respect to oxygenation. • Well oxygenated viable & dividing • Well oxygenated viable & non-dividing • Poorly oxygenated viable & non-dividing • Anoxic and/or necrotic non-viable

23. Tumor Hypoxia • There are two types of hypoxia • Transient Hypoxia • Intermittent in nature • Can be quite severe • Permanent Hypoxia • Unrelieved hypoxia • Severe to the point of causing cell death

24. Tumor Hypoxia • Intermittent Hypoxia • Caused by vascular spasm • Spasm usually at the arteriole level • Due to lack or neurologic control of vessels • May be mediated by vasopressors secreted by the tumor • Increases radiation resistance • Increase resistance to some drugs

25. Tumor Hypoxia • Permanent Hypoxia • Occurs when tumor growth outstrips vascular supply • Hypoxic cells are physically displaced from vessels. • Oxygen diffusion distance varies with metabolism but beyond 100 microns hypoxia is probably profound. • Tumor pressure on surrounding tissues may further impede blood supply.

26. Tumor Hypoxia

27. Tumor Hypoxia

28. Tumor Hypoxia

29. Tumor Hypoxia • Hypoxic cells are radiation resistant • Decreased Oxygen fixation of injury • Permits repair to proceed • Must be relatively profound. • O2 tension below 3mmHg • Present during main phase of repair • Hypoxic cell D0 2.5-3.0 x oxic cells • Favors tumors as normal tissue are oxic

30. Tumor Hypoxia

31. Tumor Hypoxia • Hypoxia not protective against single hit double strand break injury. • Linear part of curve is maintained • Hypoxia less of a concern with high LET • Hypoxic cells are not in cycling pool. • Cell division dependent on normal oxygen

32. Reoxygenation • Refers to reestablishing Oxygen supply to hypoxic cells. • Occurs spontaneously with transient hypoxia when vasospasm releases • Occurs through oxic cell death in chronic hypoxia. • Promoted by treatment schemes or drug interventions but mechanism the same.

33. Reoxygenation • Necessary in Radiation therapy • Normal tissues are oxygenated. • Oxygenated normal tissues are more sensitive to radiation than hypoxic tumor cells • Irradiation of tumors usually requires irradiation of normal tissues. • Normal tissue tolerance limits radiation dose.

34. Reoxygenation • Accomplished by fractionation • Oxic cells preferentially killed by radiation • Cells in cycling pool • Cells with normal oxygen tension • Cells with normal nutrition • Cells with normal pH • Poorly oxygenated cells move into oxic zone.

35. Normal Tissue Tolerance • Inherent radiosensitivity of cells • Repair capability of cells • Cell cycle time of critical cell line • Repopulation potential of cells • Size of the radiation field • Finely fractionated dose tolerance levels of normal tissues varies from about 10 gray to 75 gray

36. Normal Tissue Tolerance • Inherent radiosensitivity of tissues • Apparent differences in radiosensitivity are largely due to redundancy of cells • At the cellular level mammalian cells most have the same sensitivity within a fairly narrow range (D0~ 1.5-2.0 Gy) • Hypoxia does not play a significant role • Other factors such as drugs can modify the inherent sensitivity of some tissues

37. Normal Tissue Tolerance • Repair capability of critical line • Late responding tissues generally more repair • Early responding tissues generally less repair • Critical cell line may not be early responder • Repair capability may be altered by outside influences such as hyperthermia

38. Normal Tissue Tolerance • Cell cycle time of the critical cell line • Apparent tolerance may only be due to slow cell cycle times • Dose rate effect may allow tolerance in rapidly dividing cells do to repopulation • Relative abundance of critical cells may increase tolerance

39. Normal Tissue Tolerance • Repopulation potential of tissue cells • Tissues with many blast cells have greater repopulation potential. • Particularly if dose rate is low • Tissues composed of hierarchical type cells usually have greater repopulation potential • RPM and Flexible type cells may have limited repopulation potential

40. Normal Tissue Tolerance • Size of the radiation field • Small fields allow healing by ingrowth of cells from non irradiated tissue. • Small fields less likely to irradiate whole organ • Small fields permit revascularization by invasion from periphery. • Large field increase scatter and dose to adjacent tissue with potential influence on damage to target tissue.

41. Normal Tissue Tolerance • Dose fractionation scheme • Fractionation favors repair • Repair greatest in late responding tissue • Dose rate effect favors repopulation • Fractionated dose reduces injury in most normal tissues.

42. Radiocurability of Tumors • Tumors display a wide range of apparent sensitivity to radiation injury • Generally speaking the same factors at work in normal tissues are also at work in tumors • Hypoxia, if present, will reduce injury • Size and type of tumor also influences the rate of radiation control

43. Tumor Curability • Practices employed in radiation therapy are designed to promote normal tissue survival and increase tumor tissue death. • The difference between normal tissues and tumor tissue is generally small. • The therapeutic gain is the ratio of tumor death to normal tissue death