This document discusses various mechanisms of cancer development and treatment strategies: 1. Cancer cells acquire mutations that allow them to evade normal cell cycle controls and proliferate uncontrollably. Key genes like Ras, Rb, p53 and telomerase are often mutated. 2. Advanced cancer cells recruit blood vessels to fuel their growth, avoid dependence on growth factors, and become invasive. They can also manipulate the immune system to avoid detection. 3. New targeted cancer treatments aim to deliver chemotherapy directly to cancer cells using nanoparticles coated with proteins that bind specifically to receptors on tumor cells. Immunotherapy approaches reprogram a patient's immune cells to attack the cancer. 4. Understanding the hallmarks of

2. Muscle tropomyosin

3. Normally binds to actin filaments

4. Functions in a dimerized form, forming a polypeptide where each of two peptides is wound around one another and Ns and Cs are aligned

5. Interacts with actin for muscle contraction

6. In gene rearrangement, MusTrop is exchanged for EXC domain of TRK receptor

7. TRK normally binds to GFs like nerve GFs, BDNF, Neurotrophins

8. Single polypeptide of Trk receptor interacts with one region of that GF while the other interacts with another region of GF, dimerizing to make a functioning Trk receptor

9. In this example, a single polypeptide of MusTro is expressed with or instead of the EXC domain of a single Trk receptor

10. When MusTrop dimerizes, it dimerizes the receptor and bring two polypeptides together so that the cytoplasmic regions are juxtaposed

11. Autophosphorylate one another acting as if always bound by GFs

12. Oncoprotein now is continually active, activating Ras signaling and driving cell mitosis

13. PDGF receptor

14. Platelet derived growth factor

15. GF that binds to Trk receptor under normal circumstances, turning on kinase signaling

16. In the oncoprotein form: (driving cell mitosis)

17. Tel, a transcription factor, is coded and expressed as EXC domain of the PDGF receptor

18. Due to its structure, helix loop helix, it interacts to dimerize receptors and always on

19. Rb Protein

20. Tumor suppressor

21. Rb normally functions in absence of GF to bind E2F and restrict it from promoting gene transcription

22. GFs can activate Ras pathway

23. Stimulates signaling cascade that Pi G1 Cdk-cyclin

24. Pi Rb

25. Releasing E2F

26. Drive gene transcription

27. Proteins for S phase required are synthesized

28. Heritable mutations

29. Lead to one hit on a TSGene

30. In sperm, allele is mutated

31. Now have a single copy with functioning Rb and non-functioning Rb

32. Each cell of the body has one hit on normally functioning allele

33. Required for TSG

34. TSG regulate mitotic ability and not enhance it (must have two hits for TSG)

35. Mutations from external signals

36. Cells divide normally until individuals cells are mutated twice on the particular gene after fertilization in somatic cells

37. Ras Mutation

38. If on always

39. Continually Pi Rb to keep cell in mitotic state

40. Point mutations of Ras and Raf lead to always on

41. Mutations don’t mean that cell will divide uncontrollably

42. P53 – guardian of cell

43. Shut cell down by upregulating ihibitors of the Cdk-cyclin proteins, going to G0

44. P21 is the Cdk inhibitor

45. Inhibits function of G1 Cdk-cyclins by taking up the ATP binding site of the G1 Cdk cyclin so it can’t Pi Rb

46. Upregulates PUMA

47. Binds to Bcl2

48. Leads cell to apoptosis

49. Mechanisms to recognize DNA damage

50. Tumors are loss of ability to recognize DNA damage

51. Cell Stress

52. Responses of cells to stress that can be recognized by cell and lead to cell cycle arrest or death

53. Treatment induced stress can lead to mutations that can lead to cell death

54. Can induce so much damage that the cell will die instead of mitosis

55. Sometimes the treatment for cancers is to also induce mutations so much that it will die instead of go through mitosis

56. Can cause mitotic failure

57. Instable MTs and can’t polymerize/associate with chromosomes and detach at anaphase

58. Can drive autophagy or necrosis

59. Radiation or chemotherapy

60. Tumoregenic Stress

61. Harms cell way toooooo much

62. Limitation to GFs, oxygen and nutrients

63. Angiogenesis can deal with this lack of nutrients

64. Immune responses

65. Though to fight tumoregenic cells

66. DNA damage

67. There’s a limit though

68. Oncogene activation

69. Telomere shortening

70. Related to aging

71. Progeria disease (premature aging)

72. Regulate mitosis (Hayflick limit)

73. Telomere shortening causes cells to reach the Hayflick limit before senescence

74. Telomerases shorten ends of telomeres until too short to replicate cell

75. In cancer cells, telomeres don’t shorten

76. In normal cells

77. EXC signal leads to DNA damage

78. Repaired by p53 or other mechanisms

79. Or undergoes Apoptosis

80. In cancer cells

81. Ionizing radiation causes DNA damage

82. No cell cycle arrest if that mutation is not recognized because p53 is not functional and cell divides to become cancerous

83. Cell can die if damage is severe

84. Used for radiation therapy

85. P53

86. Functioning p53 genes

87. Treating cells with chemo drugs

88. Undegoe apoptosis

89. Heterozygous mutation

90. Treat with chemo

91. Some cells don’t divide

92. Both alleles are knocked out, no functioning p53

93. Treat cells with chemo

94. Look just like normal cells (in these particular chemo agents 5-fluorouracil, etoposide, adriamycin)

95. Moral:

96. May cause secondary side effects with chemo drugs and not reducing cancer cells and may not affect tumor cells, so which treatments are best then?

97. Mutations

98. Normal cell undergoes cell division and divide to reach hayflick limit

99. Successive mutations

100. Lead to oncogenic transofmraiton and then malignancy

101. Cell divides with properties passed down to progeny

102. Can mutate more

103. Cancer Smart Bombs

104. Try to target delivery mechanisms to cancer cells

105. There are two types of therapies of these

106. Nanoparticles

107. Coated with chemo drugs (anti-cancer drugs) Docetaxel

108. Also coated with proteins that act as homing receptors for these chemo packets

109. These homing receptors will target these nanonparticle packaged with chemo drugs to specific cells of interest

110. Work like immune cells

111. Homing receprots on immune cells will target specific types of immune cells to inflamed tissue, but to particular sites of tissue where the receptor recognizes a particular protein on surface of that cell

112. Coated with aptomers (homing receptors)

113. Short RNA sequences that bind to proteins

114. Put on surface of packages/cancer drugs

115. Target drug to receptors on cancer cells

116. Study: prostate cancer cells

117. Receptor: PSMA protein

118. Mucosal adresin protein that has globular domains

119. RNA binds to it and delivers drug to prostate cancer cell

120. Endocytosed so drug comes in and hopefully kills prostate cell

121. Docetaxel nanoparticle (np aptomer)

122. Targets prostate cells

123. Can just target cancer cells

124. Manipulates a person’s immune system

125. Took melanoma patients

126. Took out immune cells

127. Virally infected immune cells with a virus that would express a protein that would target them to the melanoma cancer cells

128. While generating ‘super immune cells’ outside, they irradiated the person to destroy the immune system and replaced with super immune system designed through viral infection (and cytokine activation for reproducing normal immune cells)

129. Two of 17 showed a sustained decrease in melanoma

130. Considered successful and worked!

131. Benefits

132. Don’t have rejection because it’s the person’s own immune system

133. Hallmarks of Cancer

134. Characteristics of tumor cells

135. Tumor cell recruits blood vessels (increased angiogenesis as well)

136. Cells less dependent on GFs

137. Enhanced signaling (such as kinase signaling)

138. Unregulated cell mitosis

139. May become invasive to become malignant

140. Immune function contributes to tumor progression (Kim et al)

141. Study showed that they have the ability to recruit immune cells, called macrophages, that are activated in such a way that they do two things to promote tumor formation:

142. Increase in cytokine production

143. Change in ECM proteins (Versican)

144. This protein (Versican) is secreted by macrophages in high concentrations and also upregulate production of cytokines

145. These characteristics favor tumor cell growth where the cells are healthier