Hallmarks Naralys Batista January 7, 2014

1. HallmarksNaralys BatistaJanuary 7, 2014 Funding for this workshop was provided by the program “Computational Modeling and Analysis of Complex Systems,” an NSF Expedition in Computing (Award Number 0926200).

2. Evolution of a Species • is the change in the inherited characteristics of biological populations over successive generations. • Evolutionary processes give rise to diversity at every level of biological organization, including species, individual organisms and molecules such as DNA and proteins.

3. Natural Selection • is the gradual process by which biological traits become either more or less common in a population as a function of the effect of inherited traits on the differential reproductive success of organisms interacting with their environment. • “Survival of the fittest.”

4. Evolution of Cells Cells of the human body are constantly growing, moving, dividing, and dying. • The steady occurrence of division allows for the possibility and reality of genetic mutations. • The accumulation of genetic mutations can lead to either suitable conditions for the human or conditions that compromise the function of the body.

5. Cancer • Is the unregulated growth of cells, dividing and growing uncontrollably. • Stage 0 – A cluster of cancer cells that is in the position where it started. It poses little or no threat to life. • Stage 1- Localized cancer. Cancer cells begin to pass through the thin fibrous membrane that separates cancer tissue from healthy tissue. Indicates that growing cancer cells may threaten life. • Stage 2 & 3 – Regional spread. Cancer daughter cells begin to invade through lymph vessels and get caught in lymph nodes.** • Stage 4- Distant Spread. Cancer cells get into the blood stream and go elsewhere in the body and form colonies in other organs.

6. Accumulation of Mutations • Cancer requires the accumulation of various genetic mutations that allow for the proliferation of these cancerous cells. • Hallmarks outlines 6 acquired capabilities that are shared by most and perhaps all types of human cancer. • Self-sufficiency in growth signals • Insensitivity to anti-growth signals • Tissue invasion & metastasis • Limitless replicative potential • Sustained angiogenesis • Evading apoptosis

7. Self Sufficiency in Growth Signals • Healthy cells require growth signals to move from G0 into G1, an active proliferative state. These signals are usually received from neighboring tissue. • These signals are transmitted into the cell by transmembrane receptors that bind distinctive classes of signaling molecules: diffusible growth factors, extracellular matrix components, and cell-to-cell adhesion/interaction molecules. ** • Tumor cells are liberated from this dependence on outside growth signals. • These cells synthesize their own GS creating autocrine stimulation. • In many instances Growth Factor receptors (Tyrosine Kinase Receptors) are overexpressed in many cancers, which causes cell to become hyperresponsive to levels of GF that would not normally trigger proliferation

8. Self Sufficiency in Growth Signals • Proliferation can also be caused independent from ligands if the structural integrity of GF receptors is altered. • The issue that arises from the acquired Growth Signal autonomy is the alteration of downstream pathways (e.g. SOS-Ras-Raf-MAPK pathway) that control and influence proliferation. • Altered Ras proteins can enable the release of signals into the cells without stimulation from upstream regulators. • Altered Ras proteins are found in about half of the tumors studied of human colon carcinomas.

9. Insensitivity to Antigrowth Signals • In healthy tissue, there are Antiproliferative signals that keep cells in cellular quiescence. These Growth Inhibitory signals act just like their counterparts and are received by cell surface receptors coupled to intracellular signaling circuits. • These Growth Inhibitory signals can pull cells from active proliferation (G1) into the quiescent state (G0), from which they can reemerge on some future occasion when they are permitted by GS. • A normal cell’s proliferative potential can be permanently relinquished by being induced into a postmitotic state, which usually occurs in differentiation. **

10. Insensitivity to Antigrowth Signals • Cancer cells must evade these antiproliferative signals if they are to prosper within the body. • These cells may turn off expression of integrins that send antigrowth signals and instead favor those that have progrowth signals. • The antigrowth circuit which influences the cell cycle is disrupted in a majority of cancer and tissues lose this essential tumor suppression characteristic. • Our healthy cells also limit cell multiplication by instructing cells to become differentiated and therefore in postmitotic states. • Cancer cells use various strategies to avoid or reverse this terminal differentiation.

11. Evading Apoptosis • The apoptotic program, programmed cell death, is present in virtually every cell in the body. Once triggered by physiologic signals, the program follows a set of precise choreographed steps leading to the cells demise. • Intracellular sensors monitor the cell’s wellbeing. When detecting abnormalities (DNA damage, signaling imbalance by oncogene action, survival factor insufficiency, or hypoxia) and begins death pathway. • A potent catalyst of apoptosis is cytochrome C, a proapoptotic signal, is released by the mitochondria. • Tumor suppressor proteins can elicit apoptosis by upregulating expression of proapoptotic proteins in response to sensing DNA damage • Ultimately intracellular proteases, caspases, are the effectors of apoptosis.

12. Evading Apoptosis • Apoptosis is a great barrier to cancer. In a 1972 study, in populations of cells that were rapidly growing there was massive apoptotic activity. • This aggressive apoptotic activity shows that mutant cells that arise and multiply largely can still be controlled and removed from the body’s tissues if apoptosis is able to occur. • Cells that lose this behavior often mutate a gene that produces p53 which is a key component of the DNA damage sensor that can induce the apoptotic effector cascade. • Apoptotic program is lost of the cell’s sensors are damaged and cannot relay the signal that conditions in the cell are abnormal.

13. Evading Apoptosis • Evidence has been found that the regulatory and effector components of the apoptotic signaling circuitry are redundant. • “This redundancy holds important implications for the development of novel types of antitumor therapy since tumor cells that have lost proapoptotic components are likely to retain other similar ones.” • A treatment restoring the apoptotic defense mechanism inherent in cells is a primary goal.

14. Limitless Replicative Potential • Most kinds of mammalian cells have an intrinsic program that determines a finite replicative potential. Senescence is the process by which cell populations stop growing after their allotted number of doublings. • Telomeres, the nonsensical sequences of base pairs at the end of chromosomes, regulate the amount of doubling in each generation of cells. • In each cell cycle 50-100 base pairs are lost. Eventually essential chromosomal DNA will be impaired through this shortening and the generation will effectively end.

15. Limitless Replicative Potential • In malignant cells the telomeres are maintained by upregulating the expression of the telomerase enzyme, which adds hexanucleotide repeats onto the telomeric end of DNA. • Telomeres are then kept at a critical threshold allowing for the unlimited multiplication of their cells. • Senescence is a protective mechanism that can be activated by cells with shortened telomeres and force them into a G0 state in which they won’t be able to further proliferate.

16. Sustained Angiogenesis • All cells in a tissue require a nearby (within 100 μm) blood supply, a capillary blood vessel, to supply essential compounds to the cell (oxygen, nutrients). • Once tissue is formed, new blood vessels are formed through angiogenesis to provide access to nutrients. • Angiogenesis is encouraged or blocked by counterbalancing positive and negative signals. • Vascular Endothelial Growth Factor (VEGF) encourages, throbospondin-1 inhibits.

17. Sustained Angiogenesis • Malignant cells initially lack angiogenic ability and must acquire this capability in order to become macroscopic. • An “angiogenic switch” must be turned on to induce and sustain angiogenesis by changing the balance of angiogenesis inducers and inhibitors. • Angiogenesis was found to be activated in tumors prior to their appearance as large full blown tumors. • Studies have been executed where anti-VEGF antibodies were able to impair the growth of tumors in mice, providing evidence to show the necessity of angiogenesis of explosive growth of tumors. • VEGF (angiogenesis encourager) inhibitors are now being tested in clinical trials to downregulate proteins that aid in angiogenesis of tumors.

18. Tissue Invasion & Metastasis • Cell-cell adhesion molecules (CAMs) are proteins that tether cells to their surrounding tissues. • Many of the adherence interactions convey regulatory signals to the cell. • For example, E-cadherin, the most widely observed CAM, bridges the transmission of antigrowth signals. • When E-cadherin expression was upregulated in cancer cells, invasion and metastasis were impaired. • When malignant cells lose their capability to use CAMs, the cells break off from the tumor and are able to travel to new sites in the body.

19. Tissue Invasion & Metastasis • After malignant cells are able to detach from the primary body of the tumor successful colonization of new sites requires adaptation to the new microenvironment. • The cancer cells facilitate this adaptation by shifting the expression of extracellular proteins (integrins) to ones that are favored by the ECM of the new site. • If malignant cancers are able to upregulate proteases, they can degrade the matrix of nearby cells and invade the stroma where they will have access to blood vessel walls.

20. A Different Approach to Cancer • The natural selection that occurs within the body to create an aggressive cancer is difficult to understand as one disease and also difficult to treat as one disease.