Question

Hallmark of cancer: inducing angiogenesis

a) Describe a pathway that forms part of this hallmark (inducing angiogenesis) with important proteins and proteins frequently mutated in cancer and b) describe a way in which you could influence this pathway, the effect that this should have on cancer from a pathway perspective and any possible issues with such a drug such as resistance, selectivity, or specificity.

Answer 1

The hallmarks of cancer:
Eight functional capabilities are the hallmarks of cancer. They are thought to be acquired by developing cancers in the course of the multistep carcinogenesis that leads to most forms of human cancer. The order in which these hallmark capabilities are acquired and the relative balance and importance of their contributions to malignant disease appears to vary across the spectrum of human cancers.

Sustaining Proliferative Signaling: Arguably, the most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. Normal tissues carefully control the production and release of growth-promoting signals that instruct entry of cells into and progression through the growth-and-division cycle, thereby ensuring proper control of cell number and thus maintenance of normal tissue architecture and function. Cancer cells, byderegulating these signals, become masters of their own destinies. The enabling signals are conveyed in large part by growth factors that bind cell-surface receptors, typically containing intracellular tyrosine kinase domains. The latter proceed to emit signals via branched intracellular signaling pathways which regulate progression through the cell cycle as well as cell growth; often, these signals influence yet other cell-biologic properties, such as cell survival and energy metabolism

Somatic Mutations Activate Additional Downstream Pathways
DNA sequencing analyses of cancer cell genomes have revealed somatic mutations in certain humantumors which predict constitutive activation of the signaling circuits, cited previously, which are normally triggered by activated growth factor receptors. The past 3 decades have witnessed the identification in tens of thousands of human tumors of mutant, oncogenic alleles of the RAS proto-oncogenes, most of them have sustained point mutations in the 12th codon, which results in RAS proteins that are constitutively active in downstream signaling. Thus, more than 90% of pancreatic adenocarcinomas carry mutant K-RAS alleles. More recently, the repertoire of frequently mutated genes has been expanded to include those encoding the downstream effectors of the RAS proteins. For example, we now know that ~40% of human melanomas contain activating mutations affecting the structure of the B-RAF protein, resulting in constitutive signaling through the RAF to the mitogen-activated protein–kinase pathway. Similarly, mutations in the catalytic subunit of phosphoinositide 3-kinase isoforms are being detected in an array of tumor types; these mutations typically serve to hyperactive the PI3K signaling pathway, causing in turn, excess signaling through the crucial Akt/PKB signal transducer. The advantages to tumor cells of activating upstream versus downstream signaling remain obscure, as does the functional impact of cross-talk between the multiple branched pathways radiating from individual growth factor receptors.

Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative Signaling

Recent observations have highlighted the importance of negative-feedback loops which normally operate to dampen various types of signaling and thereby ensure homeostatic regulation of the flux of signals coursing through the intracellular circuitry. Defects in these negative-feedback mechanisms are capable of enhancing proliferative signaling. The prototype of this type of regulation involves the RAS oncoprotein. The oncogenic effects of mutant RAS proteins do not result from a hyperactivation of its downstream signaling powers; instead, the oncogenic mutations affecting RAS genes impair the intrinsic GTPase activity of RAS that normally serves to turn its activity off, ensuring
that active signal transmission is transient; as such, oncogenic RAS mutations disrupt an autoregulatory negative-feedback mechanism, without which RAS generates chronic proliferative signals.

Excessive Proliferative Signaling can Trigger Cell Senescence
Early studies of oncogene action encouraged the notion that ever-increasing expression of such genes and the signals which are released by their protein products would result in proportionately increased cancer cell proliferation and, thus, tumor growth. More recent research has undermined this notion, in that it is now apparent that excessively elevated signaling by oncoproteins, such as RAS, MYC, and RAF, can provoke counteracting responses from cells, like induction of cell death; and alternatively, cancer cells expressing high levels of these oncoproteins may be forced to enter into the nonproliferative but viable state called senescence. These responses contrast with those seen in cells expressing lower levels of these proteins, which permit cells to avoid senescence or cell death and, thus, proliferate.

Resisting Cell Death
The ability to activate the normally latent apoptotic cell-death program appears to be associated with the most types of normal cells throughout the body. Its actions in many if not all multicellular organisms seems to reflect the need to eliminate aberrant cells whose continued presence would otherwise threaten organismic integrity. This rationale explains why cancer cells often, if not invariably, inactivate or attenuate this program during their development.

7.Angiogenesis
Like normal tissues, tumors require sustenance in the form of nutrients and oxygen as well as an ability so that it can evacuate metabolic wastes and carbon dioxide. The tumor-associated neovasculature which is generated by the process of angiogenesis, addresses these needs. During embryogenesis, the development of the vasculature involves the birth of new endothelial cells and their assembly into tubes in addition to the sprouting or angiogenesis of new vessels from existing ones. Following this morphogenesis, the normal vasculature becomes largely quiescent. In the adult, as part of physiologic processes i.e. wound healing and female reproductive cycling, angiogenesis is turned on, but only transiently. In contrast, during tumor progression, an angiogenic switch is almost always activated and remains on, causing normally quiescent vasculature to continually sprout new vessels that help sustain expanding neoplastic growths. A compelling body of evidence indicates that the angiogenic switch is governed by countervailing factors
which either induce or oppose angiogenesis. Some of these angiogenic regulators are signaling proteins that bind to stimulatory or inhibitory cell-surface receptors displayed by vascular endothelial cells. The well-known prototypes of angiogenesis inducers and inhibitors are vascular endothelial growth
factor-A and thrombospondin-1
PS: Due to some technical problems we are unable to provide the second part of the answer. We therefore request you to retake the picture of that particular question and post again. If the answer that is given helps you please give a positive feedback rating. It is really very important to us.