Hallmarks of Caner Paper

Hallmark of Cancer 6

Activating Invasion and Metastasis: The best characterized alteration involved the loss by carcinoma cells of E-cadherin, a key cell-to- cell adhesion molecule. By forming adherens junctions with adjacent epithelial cells, E-cadherin helps to assemble epithelial cell sheets and maintain the quiescence of the cells within these sheets. E-cadherin is a key suppressor of this hallmark capability. Expression of genes encoding other cell-to-cell and cell-to-ECM adhesion molecules is demonstrably altered in some highly aggressive carcinomas. Conversely, adhesion molecules normally associated with the cell migrations that occur during embryogenesis and inflammation are often upregulated.

The Tumor Microenvironment

Cancer cells are the foundation of the disease; they initiate tumors and drive tumor progression forward, carrying the oncogenic and tumor suppressor mutations that define cancer as a genetic disease. Once primary tumors have formed, the CSCs, like their normal counterparts, may self-renew as well as spawn more differentiated derivatives; in the case of neoplastic CSCs, these descendant cells form the great bulk of many tumors. CSCs may represent a double-threat, in that they are more resistant to therapeutic killing and, at the same time, endowed with the ability to regenerate a tumor once therapy has been halted. Sequencing of the genomes of cancer cells microdissected from different sectors of the same tumor (Yachida et al., 2010) has revealed striking intratumoral genetic heterogeneity. Much of the cellular heterogeneity within tumors is found in their stromal compartments. Prominent among the stromal constituents are the cells forming the tumor-associated vasculature. (Endothelial cells and pericytes). The roster of tumor-promoting inflammatory cells now includes macrophage subtypes, mast cells, and neutrophils, as well as T and B lymphocytes. List of signaling molecules released by inflammatory cells that serve as effectors of their tumor-promoting actions. These include the tumor growth factor EGF, the angiogenic growth factor VEGF, and cytokines that amplify the inflammatory state, matrix-degrading enzymes. The term ''cancer-associated fibroblast'' subsumes at least two distinct cell types: (1) cells with similarities to the fibroblasts that create the structural foundation supporting most normal epithelial tissues and (2) myofibroblasts, whose biological roles and properties differ markedly from those of tissue-derived fibroblasts. Myofibroblasts transiently increase in abundance in wounds and are also found in sites of chronic inflammation. Recruited myofibroblasts and reprogrammed variants of normal tissue-derived fibroblastic cells have been demonstrated to enhance tumor phenotypes, notably cancer cell proliferation, angiogenesis, and invasion and metastasis. Tumor-associated stromal cells may be supplied to growing tumors by proliferation of preexisting stromal cells, by differentiation in situ of local stem/progenitor cells originating in the neighboring normal tissue, or via recruitment of bone marrow-derived stem/progenitor cells.

Mechanisms of Contact Inhibition and Its Evasion

Cell-to- cell contacts formed by dense populations of normal cells suppress further cell proliferation. Such ''contact inhibition'' is abolished in various types of cancer. One mechanism involves the product of the NF2 gene, long implicated as a tumor suppressor because its loss triggers a form of human neurofibromatosis. A second mechanism of contact inhibition involves the LKB1 epithelial polarity protein, which can overrule the mitogenic effects of the powerful Myc oncogene when the latter is upregulated in organized, quiescent epithelial structures. Corruption of the antiproliferative TGF-b Pathway Promotes Malignancy.

Autophagy Mediates Both Tumor Cell Survival and Death

In analogy to TGF-b signaling, which can be tumor suppressing at early stages of tumorigenesis and tumor promoting later on, autophagy seems to have conflicting effects on tumor cells and thus tumor progression. Autophagy can be induced during nutrient deficiency to keep the cell alive.

The Daunting Complexity of Metastatic Colonization

Metastasis can be broken down into two major phases: the physical dissemination of cancer cells from the primary tumor to distant tissues, and the adaptation of these cells to foreign tissue microenvironments that results in successful colonization, i.e., the growth of micrometastases into macroscopic tumors. Colonization is unlikely to depend exclusively on cell-autonomous processes. Instead, it almost certainly requires the establishment of a permissive tumor microenvironment composed of critical stromal support cells. It is considerably more complex and diverse than the preceding steps of metastatic dissemination.

Necrosis Has Proinflammatory and Tumor-Promoting Potential

Necrotic cell death releases proinflammatory signals into the surrounding tissue microenviron- ment, in contrast to apoptosis and autophagy, which do not. As a consequence, necrotic cells can recruit inflammatory cells of the immune system, which can be actively tumor promoting, given that such cells are capable of fostering angiogenesis, cancer cell proliferation, and invasiveness.

Therapeutic Targeting of Genomic Instability and Mutation

PARP Inhibitors

Therapeutic Targeting of Resisting Cell Death

Proapoptotic BH3 mimetics

Programming of Hallmark Capabilities by Intracellular Circuitry

The intracellular integrated circuit can be segmented into distinct subcircuits, each of which is specialized to support a discrete cell-biological property in normal cells and is reprogrammed in order to implement a hallmark capability in cancer cells. There exists crosstalk between the individual subcircuits. For example, certain oncogenic events can affect multiple capabilities.

4 Ways Cancer Cells sustain proliferative signaling.

They may produce growth factor ligands themselves. Send signals to normal cells within the supporting tumor-associated stroma, which reciprocate by supplying the cancer cells with various growth factors. Receptor signaling can also be deregulated by elevating the levels of receptor proteins displayed at the cancer cell surface, rendering such cells hyperresponsive to otherwise-limiting amounts of growth factor ligand. Constitutive activation of components of signaling pathways operating downstream of these receptors, obviating the need to stimulate these pathways by ligand-mediated receptor activation.

Enabling Characteristic 2

Tumor-Promoting Inflammation: Some tumors are densely infiltrated by cells of both the innate and adaptive arms of the immune system and thereby mirror inflammatory conditions arising in non-neoplastic tissues . Inflammation can contribute to multiple hallmark capabilities by supplying bioactive molecules to the tumor microenvironment, including growth factors that sustain proliferative signaling, survival factors that limit cell death, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT. Additionally, inflammatory cells can release chemicals, notably reactive oxygen species, that are actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward states of heightened malignancy.

epithelial-mesenchymal transition (EMT)

A means by which transformed epithelial cells can acquire the abilities to invade, to resist apoptosis, and to disseminate. It can be activated transiently or stably, and to differing degrees, by carcinoma cells during the course of invasion and metastasis. Carcinoma cells that have undergone an EMT during initial invasion and meta- static dissemination may pass through the reverse process, and revert to a noninvasive trait, termed the mesenchymal-epithelial transition (MET).

Therapeutic Targeting of Evading Growth Suppressors

Cyclin-dependent kinase inhibitors

Hallmarks of Cancer Definition

Distinctive and complementary capabilities that enable tumor growth and metastatic dissemination.

Therapeutic Targeting of Sustaining Proliferative Signaling

EGFR inhibitors

THERAPEUTIC TARGETING

Each of the core hallmark capabilities is regulated by partially redundant signaling pathways. Consequently, a targeted therapeutic agent inhibiting one key pathway in a tumor may not completely shut off a hallmark capability, al- lowing some cancer cells to survive with residual function until they or their progeny eventually adapt to the selective pressure imposed by the therapy being applied. In response to therapy, cancer cells may also reduce their dependence on a particular hallmark capability, becoming more dependent on another.

Cancer Hallmark 4

Enabling Replicative Immortality: In normal cells, repeated cycles of cell division lead first to induction of senescence and then, for those cells that succeed in circumventing this barrier, to a crisis phase, in which the great majority of cells in the population die. The length of telomeric DNA in a cell dictates how many successive cell generations its progeny can pass through before telomeres are largely eroded and have consequently lost their protective functions, triggering entrance into crisis. Telomerase, the specialized DNA polymerase that adds telomere repeat segments to the ends of telomeric DNA, is almost absent in nonimmortalized cells but expressed at functionally significant levels in the vast majority (90%) of human cancer cells. The eventual immortalization of rare variant cells that proceed to form tumors has been attributed to their ability to maintain telomeric DNA at lengths sufficient to avoid triggering senescence or apoptosis, achieved most commonly by upregulating expression of telomerase.

Hallmark of Cancer 2

Evading Growth Suppressors: Cancer cells must also circumvent powerful programs that negatively regulate cell proliferation; many of these programs depend on the actions of tumor suppressor genes. The two prototypical tumor suppressors encode the RB (retinoblastoma-associated) and TP53 proteins. The RB protein integrates signals from diverse extracellular and intracellular sources and, in response, decides whether or not a cell should proceed through its growth-and-division cycle. It is a critical gatekeeper in of cell cycle progression. Whereas RB transduces growth-inhibitory signals that originate largely outside of the cell, TP53 receives inputs from stress and abnormality sensors that function within the cell's intracellular operating systems: if the degree of damage to the genome is excessive, or if the levels of nucleotide pools, growth-promoting signals, glucose, or oxygenation are suboptimal, TP53 can call a halt to further cell-cycle progression or trigger apoptosis.

Emerging Hallmark 2

Evading Immune Destruction: Evasion by cancer cells from attack and elimination by immune cells; this capability highlights the dichotomous roles of an immune system that both antagonizes and enhances tumor development and progression. The counterintuitive existence of both tumor-promoting and tumor-antagonizing immune cells can be rationalized by invoking the diverse roles of the immune system: On the one hand, the immune system specifically detects and targets infectious agents with the adaptive immune response, which is sup- ported by cells of the innate immune system. On the other, the innate immune system is involved in wound healing and clearing dead cells and cellular debris. The immune system operates as a significant barrier to tumor formation and progression, at least in some forms of non-virus-induced cancer. Highly immunogenic cancer cells may well evade immune destruction by disabling components of the immune system that have been dispatched to eliminate them. For example, cancer cells may paralyze infiltrating CTLs and NK cells or through the recruitment of inflammatory cells that are actively immunosuppressive, including regulatory T cells. Consistent with their expression of these diverse effectors, tumor-infiltrating inflammatory cells have been shown to induce and help sustain tumor angiogenesis, to stimulate cancer cell proliferation, to facilitate tissue invasion, and to support the metastatic dissemination and seeding of cancer cells.

Enabling Characteristic 1

Genomic Instability and Mutation: Certain mutant genotypes confer selective advantage on subclones of cells, enabling their outgrowth and eventual dominance in a local tissue environment. Some clonal expansions may well be triggered by nonmutational changes affecting the regulation of gene expression e.g., inactivation of tumor suppressor genes through DNA methylation. Cancer cells often increase the rates of mutation. The accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis - The role of TP53 is central here, leading to its being called the ''guardian of the genome.'' The catalog of defects in these caretaker genes includes those whose products are involved in (1) detect- ing DNA damage and activating the repair machinery, (2) directly repairing damaged DNA, and (3) inactivating or intercepting mutagenic molecules before they have damaged the DNA. From a genetic perspective, these caretaker genes behave much like tumor suppressor genes, in that their functions can be lost during the course of tumor progression. Defects in genome maintenance and repair are selectively advantageous and therefore instrumental for tumor progression, if only because they accelerate the rate at which evolving premalignant cells can accumulate favorable genotypes.

Therapeutic Targeting of Avoiding Immune Destruction

Immune activating anti-CTLA4 mAb

Hallmark of Cancer 5

Inducing Angiogenesis: Like normal tissues, tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide. 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. The well-known prototypes of angiogenesis inducers and inhibitors are vascular endothelial growth factor-A (VEGF-A) and thrombo- spondin-1 (TSP-1), respectively. VEGF can be upregulated by oncogene signaling. Tumor neovasculature is marked by precocious capillary sprouting, convoluted and excessive vessel branching, distorted and enlarged vessels, erratic blood flow, microhemorrhaging, leakiness. Angiogenesis is induced surprisingly early during the multi- stage development of invasive cancers.

Therapeutic Targeting of Activating Invasion and Metastasis

Inhibitors of HGF/c-Met

Therapeutic Targeting of Angiogenesis

Inhibitors of VEGF Signaling

Therapeutic Targeting of Deregulating Cellular Energetics

Inhibitors of aerobic glycolysis

Invasion-metastasis cascade

Local invasion, then intravasation by cancer cells into nearby blood and lymphatic vessels, transit of cancer cells through the lymphatic and hematogenous systems, followed by escape of cancer cells from the lumina of such vessels into the parenchyma of distant tissues (extravasation), the formation of small nodules of cancer cells (micrometastases), and finally the growth of micrometastatic lesions into macroscopic tumors, this last step being termed ''colonization.''

Traits Implicated in Invasion and Metastasis

Loss of adherens junctions and associated conversion from a polygonal/epithelial to a spindly/fibroblastic morphology, expression of matrix-degrading enzymes, increased motility, and heightened resistance to apoptosis.

Heterotypic Contributions of Stromal Cells to Invasion and Metastasis

Mesenchymal stem cells (MSCs) present in the tumor stroma have been found to stimulate invasive behavior. Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes and growth factors. Malignancies cannot be understood solely through analyses of tumor cell genomes.

Emerging Hallmark 1

Reprogramming Energy Metabolism: 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.'' 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. Glycolytic fueling has been shown to be associated with activated oncogenes (e.g., RAS, MYC) and mutant tumor suppressors (e.g., TP53). This reliance on glycolysis can be further accentuated under the hypoxic conditions that operate within many tumors. Increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids; this facilitates, in turn, the biosynthesis of the macromolecules and organelles required for assembling new cells. Interestingly, some tumors have been found to contain two subpopulations of cancer cells that differ in their energy generating pathways. These two populations evidently function symbiotically: the hypoxic cancer cells depend on glucose for fuel and secrete lactate as waste, which is imported and preferentially used as fuel by their better-oxygenated brethren.

Hallmark of Cancer 3

Resisting Cell Death

Therapeutic Targeting of Tumor-promoting Inflammation

Selective antiinflammatory drugs

Characteristics of Sustaining Proliferative Signaling

Somatic Mutations Activate Additional Downstream Pathways Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative Signaling Excessive Proliferative Signaling Can Trigger Cell Senescence

Gradations of the Angiogenic Switch

Some tumor types are highly vascularized and some are not. In some tumors, dominant oncogenes operating within tumor cells, such as Ras and Myc, can upregulate expression of angiogenic factors, whereas in others, such inductive signals are produced indirectly by immune inflammatory cells. The direct induction of angiogenesis by oncogenes that also drive proliferative signaling illustrates the important principle that distinct hallmark capabilities can be coregulated by the same transforming agents. TSP-1 as well as fragments of plasmin (angiostatin) and type 18 collagen (endostatin) can act as endogenous inhibitors of angiogenesis. Pericytes provide important mechanical and physiologic support to the endothelial cells, important for the maintenance of a functional tumor neovasculature. A Variety of Bone Marrow-Derived Cells Contribute to Tumor Angiogenesis. These include cells of the innate immune system—notably macrophages, neutrophils, mast cells - and peritumoral inflammatory cells.

Heterotypic Signaling Orchestrates the Cells of the Tumor Microenvironment

Stepwise progression is likely to depend on back-and- forth reciprocal interactions between the neoplastic cells and the supporting stromal cells. Incipient neoplasias begin the interplay by recruiting and activating stromal cell types that assemble into an initial preneoplastic stroma, which in turn responds reciprocally by enhancing the neoplastic phenotypes of the nearby cancer cells. The cancer cells, which may further evolve genetically, again feed signals back to the stroma, continuing the reprogramming of normal stromal cells to serve the budding neoplasm; ultimately signals originating in the tumor stroma enable cancer cells to invade normal adjacent tissues and disseminate. The succession of reciprocal cancer cell to stromal cell interactions that defined multistep progression in the primary tumor now must be repeated anew in distant tissues as disseminated cancer cells proceed to colonize their newfound organ sites.

Hallmark of Cancer 1

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 into and progression through the cell growth- and-division cycle. Cancer cells, by deregulating 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.

Hallmarks of Cancer

Sustaining proliferative signaling Evading growth suppressors Activating invasion and metastasis Enabling replicative immortality Inducing angiogenesis Resisting cell death

Tumor Supressor Genes

TP53 induces apoptosis in response to substantial levels of DNA breaks and other chromosomal abnormalities. Tumor cells evolve a variety of strategies to limit or circumvent apoptosis. Most common is the loss of TP53 tumor suppressor function. Alternatively, tumors may achieve similar ends by increasing expression of antiapoptotic regulators or of survival signals, by downregulating proapoptotic factors (Bim, Puma), or by short-circuiting the extrinsic ligand-induced death pathway.

Therapeutic Targeting of Enabling Replicative Immortality

Telomerase Inhibitors

Distinct Forms of Invasion May Underlie Different Cancer Types

The EMT program regulates a particular type of invasiveness that has been termed ''mesenchymal.'' ''Collective invasion'' involves nodules of cancer cells advancing en masse into adjacent tissues and is characteristic of, for example, squamous cell carcinomas; interestingly, such cancers are rarely metastatic. 'amoeboid'' form of invasion: individual cancer cells show morphological plasticity, enabling them to slither through existing interstices in the extracellular matrix rather than clearing a path for themselves, as occurs in both the mesenchymal and collective forms of invasion.

Telomerase

The delayed acquisition of telomerase function serves to generate tumor-promoting mutations, whereas its subsequent activation stabilizes the mutant genome and confers the unlimited replicative capacity that cancer cells require in order to generate clinically apparent tumors. Capable of enhancing cell proliferation and/or resistance to apoptosis.