Genetics chp. 16 Cancer Genetics

oxidative stress

- defined: reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. -The anaerobic process is called glycolysis. The paradox is that cancer cells rely on glycolysis even if oxygen is available. This phenomenon is called aerobic glycolysis or the Warburg effect.

Limitless replicative protential

-Activate telomerase to restore and maintain telomeres at the end of chromosomes -Protect their chromosomes- retain the ability to divide over and over again

inducing angiogenesis *

-Both Metastatic & Uncontrolled cell growth -Balance of angiogenesis is well balanced by inhibitors (the statins & thrombospondin-1) and activators (VEGF, FGFs, EGF, LPA) In tumors, there is an increase in growth factors that promote angiogenesis; normal vessel formation grows into tumor to provide nutrients to cancer cells Full cycle of angiogenesis results in tumor vascularature (vascularature is the vascular system of a part of the body and its arrangement).

evading apoptosis (cell death)

-Normally apoptosis triggered in response to normal development and excess growth -Pathway to apoptosis is disabled (mutation of p53)

self-sufficiency in growth signal

-Secrete growth factors that stimulate own growth -Increase growth factor receptors -Cell surface receptor is mutated in the "on" position-constant cell growth/division

tissue invasion and metastasis

-Specific mutations activate ability of cells to metastasize -Ex. decreased cell to cell adhesion, secretion of preteases that digest surrrounding barriers, and ability to grow in new locations

evading immune surveillance

An Emerging Hallmark: Evading Immune Destruction -A second, still-unresolved issue surrounding tumor formation involves the role that the immune system plays in resisting or eradicating formation and progression of incipient neoplasias, late-stage tumors, and micrometastases. The long-standing theory of immune surveillance proposes that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors. According to this logic, solid tumors that do appear have somehow managed to avoid detection by the various arms of the immune system or have been able to limit the extent of immunological killing, thereby evading eradication.

metabolic stress

An Emerging Hallmark: Reprogramming Energy Metabolism -The chronic and often uncontrolled cell proliferation that repre- sents the essence of neoplastic disease involves not only deregulated control of cell proliferation but also corresponding adjustments of energy metabolism in order to fuel cell growth and division. Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and there- after to carbon dioxide in the mitochondria; under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria. Otto Warburg first observed an anomalous characteristic of cancer cell energy metabolism (Warburg, 1930, 1956a, 1956b): even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed ''aerobic glycolysis.'' The existence of this metabolic switch in cancer cells has been substantiated in the ensuing decades. Such reprogramming of energy metabolism is seemingly counterintuitive, in that cancer cells must compensate for the 18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation. They do so in part by upregulating glucose transporters, notably GLUT1, which substantially increases glucose import into the cytoplasm (Jones and Thomp- son, 2009; DeBerardinis et al., 2008; Hsu and Sabatini, 2008). Indeed, markedly increased uptake and utilization of glucose have been documented in many human tumor types, most readily by noninvasively visualizing glucose uptake using posi- tron emission tomography (PET) with a radiolabeled analog of glucose (18F-fluorodeoxyglucose, FDG) as a reporter.

Insensitivity to anti-growth signals

Antigrowth signals stop unregulated growth- are inactivated in cancer

Genome Instability & Mutation *

Enabling Characteristic Changes to genome that causes cells to loose their DNA repair mechanisms Acquire new mutations

hallmarks of cancer

ILTDMP - first six -Islands lost the dolphins magnificent presence MOESES - second 6 if Moe from the Simpsons was Moses.

metastasis process

In metastasis, cancer cells break away from where they first formed (primary cancer), travel through the blood or lymph system, and form new tumors (metastatic tumors) in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor.

Warburg effect

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.

mad2

Mad2 (mitotic arrest deficient 2) is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition.

sustained angiogenesis

Stimulate angiogenesis to form their own blood supply- delivers O2 and nutrients

Limitless replicative potential or Enabling Replicative Immortality*

Uncontrolled increase in cells Modulating Replicative Potential Telomerase - RNA Reverse Transcriptase that uses RNA as a template to synthesize DNA (rather than DNA to synthesize RNA) Essential for germ/stem cells that need to proliferate for a very long time If normal cells acquire this telomerase, they will continue to replicate, potentially becoming cancerous

more info on immune surveillance

We remain perplexed as to whether immune surveillance is a barrier that virtually all tumors must circumvent, or only an idiosyncrasy of an especially immunogenic subset of them; this issue too will be resolved in one way or another.

DNA damage stress

cancer can impact people of all ages but is more likely to impact older people because DNA damage becomes more apparent in aging DNA - may need a bit more on this one.

Oxidative phosphorylation

is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy which is used to reform ATP. In most eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is probably so pervasive because it is a highly efficient way of releasing energy, compared to alternative fermentation processes such as anaerobic glycolysis.

Cell proliferation

is the process that results in an increase of the number of cells, and is defined by the balance between cell divisions and cell loss through cell death or differentiation. Cell proliferation is increased in tumours.

proteotoxic stress

proteotoxicity (plural proteotoxicities) 1. (pathology) Any impairment of cell function caused by misfolding of a protein proteotoxic means - Pertaining to, or causing, proteotoxicity.

tissue invasion and metastasis *

some cancer cells will diffuse into the circulatory system within the tumor tissue and can be transported to other parts of the body Cancer cells can't move through microvasculature & become trapped; most die, but if they survive they can grow & divide Results in 'secondary tumor' or 'distant tumor' Multiple steps need to be successful in order to achieve metastasis! (progressive growth, vascularization, invasion, detachment, embolization, survival in the circulation, arrest, extravasation, evasion of the host defense, progressive growth)

mitotic stress

what are the implications of these results for cancer biology or therapy? Since most human tumours display alterations in p53 or pRb Marcos Malumbres suggests in his article that most tumor cells have to deal with the instability generated by overexpression of Mad2.He coins the term "oncogene-induced mitotic stress" to define this feature of cancer cells. The chromosomal instability induced by oncogenes, or loss of tumor suppressor genes, must be initially a problem for the proliferation of cancer cells. Thus, tumours need to deal with the problem to grow, for instance by downregulating Mad2 or by accumulating other alterations that improve viability in tumour cells subjected to this stress. These ideas describe some additional mechanisms behind tumour growth but what are the therapeutic implications? Since most tumours are deficient in p53 and pRb pathways, it may be concluded that tumour cells are intrinsically more susceptible to chromosomal instability and increasing this instability, for instance with mitotic checkpoint inhibitors, may be more efficient in p53- or pRb-negative tumour cells; this is an interesting possibility since several of these inhibitors are now available in preclinical and clinical trials.