La ensoñación del fuego

Due to mutations in proto-oncogenes, cancerous cells exhibit dysregulated cell cycle

control, which results in sustained proliferative signaling capability. The mutations that make this signaling possible are “gain-of function” mutations in proteins that participate in growth factor

signaling cascades [13]. Mutations render these proteins that drive cell division constitutively active. Under healthy circumstances, these proteins are subject to regulatory post-translational modifications that inhibit their activity, and thus the proliferative ability of the cell. Once a gain- of-function mutation has occurred in an oncogenic protein, it becomes constitutively active, which often results in rendering the cell prone to unregulated cell division. This makes the mutated cells able to proliferate independently of the availability of resources and cell density signals that, under healthy conditions, modulate cell proliferation. This first type of DNA

mutation is absolutely necessary for the production of neoplastic cells, thus sustained proliferative signaling is the first hallmark of cancer [13].

1.13.2.2 Evasion of growth suppressors

Although “gain-of-function” mutations are critical for the production of cancer cells, they are not sufficient for the total conversion of healthy cells to fully neoplastic cells. As mentioned previously, transformation of healthy cells to cancerous cells requires not one, but two mutation events. The first mutation event primes the cells for unchecked cell division, but can be overcome by the activation of tumor suppressor genes. Therefore mutation of the tumor suppressor genes to a “loss-of-function” phenotype is the second required step in cell transformation. The function of tumor suppressor genes is to control cell proliferation, and generally including checkpoint

proteins including: cyclin-dependent kinase inhibitors, hormone receptors, proteins that promote cellular apoptosis, and DNA repair proteins [13]. Mutations in these genes render the proteins inactive, making them unable to participate in proliferation checkpoint regulations and DNA repair coordination [13]. After overcoming this final obstacle in checkpoint regulation, the newly transformed cells are capable of proliferating unchecked until they can be recognized and cleared by the immune system.

1.13.2.3 Resistance of cell death programs

The third hallmark of cancer is the ability for the cells to resist programmed cell death. Apoptosis is a critical pathway for regulating cell damage and overall health. Without apoptosis, cells lose their ability to respond to ‘danger’ signals, and gain the ability to escape removal by the immune system. The accumulation of mutations in oncogenes resulting from the functional loss of the tumor suppressor proteins results in the buildup of apoptotic stresses. In healthy cells, the collection of apoptotic stresses set off the apoptotic cell death cascade, ultimately resulting in the activation of pro-caspases 8 and 9 [13]. Activation of these molecules leads to widespread

proteolytic activity, which signals the exposure of apoptotic signals on the outer leaflet of the cell membrane, and eventual uptake by phagocytes. A defining characteristic of cancer cells is that they evolve ways to escape succumbing to the apoptotic pathway [13]. Many proteins within the cell act as sensors to detect signs that the cell is in trouble: DNA damage, viral infection, killer lymphocyte recognition, etc. These signals function to trigger the onset of apoptosis by

“inhibiting the inhibitor.” In other words, once the alarm is tripped and the cell senses that there is a problem, it enables activity of the apoptotic program, which results in a shift toward cellular controlled cell death [13]. The ability to escape the apoptotic pathway is an especially important function of tumor cell immune evasion, as many immune cells use activation of death domain- containing receptors to trigger apoptosis as a way to eliminate tumor cells from the tissue [91].

1.13.2.4 Enabling replication immortality

Neoplastic cells undergo cell replication paying no deference to the health of the cell or the resources available to the cell. As mentioned previously, the ability to resist cell death programs is partially responsible for continued cell division, however there are other pathways that, when corrupted, add to this division ability [13]. For example, activation of telomerase activity can

circumvent the onset of senescence in neoplastic cells. Through elongation of chromosomes, the cell can avoid signaling senescence. Similarly, apoptosis is avoided through many different methods. One such method is the downregulation of apoptotic death receptors in neoplastic cells [91]. External death receptors are triggered by immune cells, which externally recognize the abnormality of the neoplastic cell and attempt to induce apoptosis. The tumor cells often inhibit expression of death receptors to avoid immune cell-induced apoptosis.

1.13.2.5 Induction of angiogenesis

Cells require a steady influx of nutrients and oxygen and a way to transport waste products away from themselves in order to survive and replicate. Tumor cells are no different in this regard, and therefore must acquire the ability to stimulate the formation of new blood vessels through a process termed angiogenesis [13]. Through a number of mechanisms, tumor cells are able to stimulate the nearby vasculature to grow new vessels and branches, which work to supply the tumor cells with precious nutrients, such as glucose and oxygen, and also act as a waste receptacle for metabolic wastes [13]. Additionally, tumor cells themselves often secrete growth factors, cytokine, and chemokines that drive changes in the immune system. In order to induce systemic changes using these secreted molecules, the tumor must recruit branches of the

circulatory system so that the secreted molecules have an entry point into major circulation. This is important because it allows tumors to signal to peripheral tissues, thereby conditioning other tissues of the host to support tumor survival. Additionally, formation of new blood vessels increases the risk for tumor cell invasion and migration [13].

Tumor cells induce angiogenesis by stimulating the nearby endothelial cells to proliferate through the secretion of growth factors. One major growth factor known to induce angiogenic changes in endothelial cells during cancer is vascular endothelial growth factor-A (VEGF-A) [5,

13]. Angiogenesis occurs early on in tumorigenesis, and is absolutely critical for the survival of the neoplastic cells. Bone marrow-derived cells are also responsible for contributing to growth factor secretion that leads to angiogenesis. Macrophages, neutrophils, and even myeloid

progenitor cells are able to infiltrate the tumor microenvironment, where they accumulate at the margins between neoplastic cells and untransformed cells [5]. Here, they function to induce angiogenesis in previously unaffected endothelial cells, and maintain the secretion of angiogenic factors to sustain the angiogenic process in the vascular tissue.

1.13.2.6 Activation of invasion and metastatic signals

Transformation of neoplastic to invasive tumor cells requires many cellular changes that are described as the epithelial-mesenchymal transition (EMT). This process is coordinated by a group of transcription factors that work together to facilitate the loss of contact inhibition and result in the ability for cancer cells to become migratory. Taken together with the ability for tumor cells to condition distal tissue to be immunosuppressive, acquisition of migratory capability allows tumor cells to establish new colonies in foreign tissue, without the risk of immediately being recognized and eliminated by the local immune response.