CELL SIGNALING AND MOTILITY (BIOL 3373) ABERRANT ceLL SIGNALING IN CANCER

1. CELL SIGNALING AND MOTILITY (BIOL 3373)ABERRANT ceLL SIGNALING IN CANCER Lecture 11

2. Cancer US 2016 cancer cases • Cancer is one of the most common diseases in the developed world. There are over 100 different forms of cancer

3. CARGINOGENESIS • Carcinogenesis is a multistep process that drives normal cells to evolve progressively towards a malignant, neoplastic state, and ultimately to acquire metastatic features. • During this process non-cancer cells develop stepwise various biological capabilities that enable them to acquire their tumorigenic potential. Note: sometimes the word carcinogenesis and oncogenesis are used interchangeably Tumorigenesis: formation of a tumor

4. Cancer HALLMARK Cancer biological capabilities have been initially categorized by Hanahan and Weinberg (2001) into six distinctive principles called cancer hallmarks thatincludes: Cell ability to proliferate unlimitedly. Evading growth suppressor cell ability to invade/metastasize Cell ability to enable replicative immortality cell ability to sustain angiogenesis cell resistance to dead From Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100: 57–70.

5. EMERGING Cancer HALLMARK and Enabling Characteristics • Cancer research field is an extremely developing field. • An increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of cancers: • the capability to reprogram cellular metabolism: • In order to support neoplastic proliferation, cancer cells switch their mitochondrial oxidative phosphorylation process towards an (an)aerobic metabolism that consists in a robust induction of glycolysis (the Warburg-effect) • The capability of cancer cells to evade immunological destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells From Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell144: 646–74. Two characteristics facilitate acquisition of Cancer hallmarks: Genomic instability and Inflammation

6. GeNETIC INSTABILITY aND CANCER • Cancer arises from the mutation of a normal gene. • It is thought that several mutations need to occur to give rise to cancer • These mutations allow cancerous cells do not self destruct and continue to divide rapidly producing millions of new cancerous cells. • These mutations “fix” the cell in the transformed state • Additional factors such as growth factors, together with aberrant cell signalling because of additional mutations lead to enhanced proliferation, angiogenesis, lack of immune regulation, invasion and metastasis. This is usually a result of: INCORRECT SIGNAL REGULATION & FAULTY SIGNAL TERMINATION

7. DNA MUTATION THAT LEADS TO CANCER Deletion Homologouschromosomes Duplication Inversion Reciprocaltranslocation Nonhomologouschromosomes

8. GENE translocation can activate an oncogene: ThePHILADELPHIA CHROMOSOME case • The reciprocal translocation between chromosomes 9 and 22 in the bone marrow is associated with chronic myelogenous leukemia

9. GENES THAT BECOME MUTATED IN CANCER: • Two classes of genes are frequently mutated in cancer: • Proto-oncogenes ( oncogenes) • Oncogenes result from mutation which turns on (activates) protooncogene to drive cancer • Tumor suppressor genes • Tumor suppressors help cause cancer when they are turned off (inactivated) by mutation

10. Cancer Mutations •Proto-oncogenes form active oncogenes by - being misplaced (e.g. by translocation) to a site where the gene is continually expressed resulting in overproduction of a protein that stimulates cell division (e.g. in Chronic Myeloid Leukemia) - By mutating to a form that is over expressed. •Cancer causing Mutations in Tumor Suppressor genes inactivate the genes so normal protein product is not formed. Mutated oncogene Tumor Suppressor gene neoplasm

11. Gene Mutations That Cause Cancer Mutations in 4 types of genes cause Cancer • Proto - oncogenes: genes that code for normal proteins used in cell division –Growth factors –Membrane Receptors for Growth Factors –Signaling Proteins (e.g. ras proto- oncogene mutates in 30% of cancers). • Tumor Suppressor genes: gene that code for proteins that help prevent uncontrolled cell division by blocking key steps (e.g. DNA replication). - Retinoblastoma susceptibilty (RB) gene - p53 gene mutates in >50% of cancers. • DNA Repair genes • Genes for Apoptosis

12. Proto-oncogenes  oncogenes: • Proto-oncogenes • Proto-oncgenes are genes that possess normal gene products and stimulate normal cell development. • Oncogenes • Oncogenes arise from mutant proto-oncogenes. • Oncogenes are more active than normal or active at inappropriate times and stimulate unregulated cell proliferation.

13. Oncogenes Are Mutated Proto-oncogenes A cell can acquire a cancer - causing oncogene from •A virus •A mutation in a proto-oncogene. Oncogenes still code for the proteins needed for cell division but they cause cancer by producing – Too much of the protein – An abnormally active protein, e.g. protein that activates division by itself – Protein that is made when it is not needed – Protein that should be made by a different (i.e. dividing) cell.

14. Oncogenes Normal genes (regulate cell growth) 1st mutation (leads to accelerated cell division) 1 mutation sufficient for role in cancer development

15. Tumor Suppressor Proteins Inhibit Cell Division & Prevent Cancer Tumor suppressor proteins are proteins that bind to checkpoint proteins to stop the cell cycle & prevent cell division if DNA is damaged. • Tumor suppressor proteins stop division of mutated cells until mistakes in DNA are repaired by enzymes. • TS proteins keep most mutations from being passed on to daughter cells & developing into cancer. • If the genes for TS proteins mutate the brake on cell division is removed cancers may result. • Two important TS proteins are the p53 protein & the RB protein.

16. Tumor Suppressor Genes Normal genes (prevent cancer) 1st mutation (susceptible carrier) 2nd mutation or loss (leads to cancer)

17. Cell cycle CDK

18. REPAIRS AHEAD The Cell Cycle Oncogenes G2 (cell growth) M (mitosis) S (synthesis) DNA repair genes G1 G0 (resting) Tumor suppressor genes Proto – oncogenes/ oncogenes induce cell cycle progression , while tumor suppressor genes inhibit it

19. CONTROL of CELL CYCLE Differentiated The Cell has 3 major G0 Cells enter “checkpoints” that are non dividing G1 sensitive to signals, the G0 phase- checkpoint G1, the G2 and the M checkpoints. • If a cell does not G1 Control pass G1 checkpoint system S it enters a non- dividing GO Phase. • Most somatic cells G2 M are in GO. • Some cells in GO (e.g. liver cells) can reenter cell cycle if M checkpoint G2 checkpoint needed. In cancer cells genes that control cell cycle have mutated so cells divide excessively producing neoplasms.

20. Normal cell cycle is controlled by signal transduction: • Growth factors bind to surface receptors (e.gtyrosine Kinase Receptors; G Protein receptors) on the cell; • Two types of growth factors: • Growth factors stimulate cell division. • Growth-inhibiting factors inhibit cell division. • Healthy cells divide only when growth factor and growth-inhibiting factor balance favors cell division. • Cancer cells divide without constraint • (e.g., mutations in growth and growth-inhibiting factor genes).

21. Regulation of cell division by signal transduction.

22. PRO-ONCOGENESAND CELL CYCLE Pro-oncogenes code for proteins that trigger Cell Cycle progression: • Intracellular Cyclins and Cyclin Dependent Kinases (CDKs) control the checkpoints. • Hormones or extracellular proteins from other cells (called Growth Factors) signal target cell to divide. - Hormones (e.g. Growth Hormone) or Growth Factors bind to receptor proteins of target cell membrane. - This triggers a molecular signaling pathway. - A series of linked proteins activate Cyclin- CDKs which Allows Cells to Pass Cell Cycle Checkpoints & divide.

23. How Growth Factors Trigger Cell Division Growth factors bind to specific receptors on the plasma membrane to trigger cell division Growth Factor or Hormone Plasma membrane Relay •G1 checkpoint prevents Proteins open damaged DNA from replicating checkpoints •Checkpoint controlled by Receptor Cyclin - CDK protein Signal Transduction Control Pathway G1 S system G2 M

24. Stimulation of Cell Division by an Oncogene Over Growth Membrane factor Hyperactive Receptor relay protein (product of Normal product of ras gene ras oncogene) Relay issues signals proteins on its own. Transcription factor (activated) DNA Transcription Protein that Translation stimulates cell division

25. The p53 Tumor Suppressor Protein The p53 tumor suppressor protein is activated when DNA is damaged. The p53 gene is called the “guardian angel of the genome” P53 protein activates Internal signalling genes for pathway proteins that •Prevent cell entering S phase •Repair DNA •Cause DNA repair Apoptosis apoptosis (if DNA is Cell cannot enter S phase irreparable)

26. Stimulation of Cell Division by a mutated tumor suppressor gene Tumor-suppressor gene Mutated tumor-suppressor gene Cancer Normal from Protein Mutation Defective, prevents of Tumor nonfunctioning cell protein Supressor division Gene if DNA is Protein damaged absent (cell division Cell division not blocked) allowed if DNA repaired Mutations accumulate in cancer cells

27. The unbalance between growth factors (pro-oncogenes) and inhibitors of growth factors induces an abnormal cell signaling and promotes cancer An elaborate integrated circuit that operates within normal cells is reprogrammed to regulate capabilities within cancer cells.

28. STEPS OF CANCER PROGRESSION

29. How do normal cells become cancerous?

30. 1. Cancer ARISES from A Genetically INSTABLE cell • Body cells replicate through mitosis, they respond to their surrounding cells and replicate only to replace other cells. Sometimes a genetic mutation will cause a cell and its descendants to reproduce even though replacement cells are not needed.In the figure The DNA of the cell highlighted has a mutation that causes the cell to replicate even though this tissue doesn't need replacement cells at this time or at this place.

31. 2. CANCER Spread IS DETERMINED BY A second mutation • The genetically altered cells have, over time, reproduced unchecked, crowding out the surrounding normal cells. At this point the cells continue to look the same as the surrounding healthy cells. After about a million divisions, there's a good chance that one of the new cells will mutated further. This cell, now carrying two mutant genes, could have an altered appearance and be even more prone to reproduce unchecked. Note: Not all mutations that lead to cancerous cells result in the cells that reproduce faster. For example, a mutation may simply cause a cell to keep from self-destructing ( Avoid normal cell Apoptosis!). All normal cells have surveillance mechanisms that look for damage or for problems with their own control systems. If such problems are found, the cell destroys itself.

32. 3. Third mutation • Over time and after many cell divisions, a third mutation may arise. If the mutation gives the cell some further advantage, that cell will grow more vigorously than its predecessors and thus speed up the growth of the tumour.

33. 4. Fourth mutation • The new type of cells grow rapidly, allowing for more opportunities for mutations. The next mutation paves the way for the development of an even more aggressive cancer. At this point the tumour is still contained.

34. 5. Breaking through the membrane • The newer, wilder cells created by another mutation are able to push their way through the epithelial tissue's basement membrane, which is a meshwork of protein that normally creates a barrier. The invasive cells in this tumour are no longer contained. At this point the cancer is still too small to be detected.

35. 6. Angiogenesis • Often during the development of earlier stages of the tumour, or perhaps by the time the tumour has broken through the basement membrane (as pictured above), angiogenesis takes place. Angiogenesis is the recruitment of blood vessels from the network of neighbouring vessels. • Without blood and the nutrients it carries, a tumour would be unable to continue growing. With the new blood supply, however, the growth of the tumour accelerates; it soon contains thousand million cells and, now the size of a small grape, is large enough to be detected as a lump

36. 7.Invasion and dispersal • The tumour has now invaded the tissue beyond the basement membrane.Individual cells from the tumour enter into the network of newly formed blood vessels, using these vessels as highways by which they can move to other parts of the body. A tumour as small as a gram can send out a million tumour cells into blood vessels a day.

37. 8. Tumour cells travel - metastasis • What makes most tumours so lethal is their ability to metastasize -- that is, establish new tumour sites at other locations throughout the body.Secondary tumours. • Metastasis is now underway, as tumour cells from the original cancer growth travel throughout the body. Most of these cells will die soon after entering the blood or lymph circulation.

38. 9. Metastasis • To form a secondary tumour, a tumour cell needs to leave the vessel system and invade tissue. The cell must attach itself to a vessel's wall. Once this is done, it can work its way through the vessel and enter the tissue. Although perhaps less than one in 10,000 tumour cells will survive long enough to establish a new tumour site, a few survivors can escape and initiate new colonies of the cancer.

39. Examples of Mutations in Signal Terminators resulting in cancer

40. WHAT CAUSE GENE MUTATION • A factor which brings about a mutation is called a mutagen. • A mutagen is mutagenic. • Any agent that causes cancer is called a carcinogen and is described as carcinogenic. A carcinogen induces Cancer due to the ability to damage the genome or to the disruption of cellular metabolic processes.

41. Factors Believed to Contribute to Global Causes of Cancer

42. Reproductive And Hormonal Risks For Cancer • Pregnancy and oral contraceptives increase a woman’s chances of breast cancer (increases risk 2-4X) • Late menarche, early menopause, early first childbirth, having many children have been shown to reduce risk of breast cancer • However, genetic factors can increase breast cancer risk >4 fold • BRCA1/2, TP53, ATM increase relative risk 4-8 fold • Family history of breast and early ovarian cancer increase risk 4 fold

43. OVARIAN CANCER RISK Nulliparity Multiparity  Birth Control Pill Use  Fertility Drug Use   BRCA1/2, one 1◦ relative

44. Most Ovarian Cancer has Unknown Etiology ?

45. Occupational And Environmental Factors • Asbestos • Nickel • Chromate • Benzene • Arsenic • Radioactive substances • Cool tars • Herbicides/pesticides Note: Each chemical or environmental carcinogen has its own unique associated tumor type and usually governed by route of exposure as well

46. Occupational And Environmental Factors

47. SocialAnd Psychological Factors • Stress has been implicated in increased susceptibility to several types of cancers • Sleep disturbances, diet, or a combination of factors may weaken the body’s immune system

48. Chemicals In Foods • Sodium nitrate when ingested forms a potential carcinogen, nitrosamine • Sodium nitrate is still used because it is effective in preventing botulism • Pesticide and herbicide residues

49. Cancer Disparities in United States From cancer.gov, 2018

50. Cancer Disparities in United States Obesity is one the strongest correlative risk factors for cancer incidence From: Introduction to Health Disparities Health Equality Peer Educator Training (HEPE) By: Travis Howlette B.S., Jeff Wisniowski B.S., MPH and Kelsey Anilionis B.S