Cancer is a disease that is typically associated with abnormal cell growth; cancerous cells have the potential to metastasise. The development of tumours can be associated to the 10 hallmarks of cancer (figure1). The 10 hallmarks of cancer are evading growth suppressors, avoiding immune destruction, enabling replicative immortality, tumour-promoting inflammation, activating invasion and metastasis, inducing angiogenesis, genome instability and mutation, resisting cell death, deregulating cellular energetic and sustaining proliferative signalling (figure1) (1).These hallmarks all influence the aggressiveness of the cancer thus highly influencing the course of treatment suggested for specific cancer types. A common treatment for cancer types is chemotherapy; chemotherapy entails the use of various drugs that target these hallmarks.
One of the hallmarks of cancer is the sustained proliferative signaling. It mainly helps in answering the questions like how cancer cells gather the ability to undergo replication at a continuous rate. Cancer cells are mainly seen to continue replication due to sustained proliferative signaling. Normal tissues are mainly seen to control the steps of production and releases of the different growth promoting signals. These signals help in instructing entry and progression of the cells through cell growth and different division cycles (1). They help in maintaining homeostasis of cell number. Thereby, they help in maintenance of normal architecture and function of tissues. Cancers mainly are different as they acquire the capability to sustain proliferative signaling by mainly increasing the production of growth factor ligands. There is also signaling of nearby normal cells that helps in providing a supply of growth factors. It also helps in increasing their levels of receptor proteins. Besides, there are also additional effects that result in contribution to the different types of proliferative capacity. Activation of the downstream pathways by mutation mainly (B-Raf, PI3K) and hyperactivity of PI3K helps in abnormal proliferation (2) (Figure 2). There is also deregulation of negative feedbacks that are mainly seen to dampen the abnormal proliferation.
It is found that in addition to the different stimulating growth signals that helps in cancer progressions; there is also a need for evasion of the different cellular negative regulation of proliferation. This acts as a cumulative factor that supports the excessive growth of the cancer cells. Under the different cellular abnormal conditions, tumor suppressor proteins and factors are present which are responsible for limiting cell growth (3). Two of the widely researched tumor suppressors are RB and TP53 that acts abnormally failing to suppress the growth of the cancer cells. The Rb protein helps in integration of signals from a diverse field of different intracellular as well as extracellular sources. In return, it decides whether a cell should or should not proceed through its growth and division cycle. . Therefore when RB pathway gets defective, it is seen to promote persistent cell proliferation. When cellular subsystems are found to be to too damaged, then Tp53 induces programmed cell death through apoptosis. This leads to a halt of cell proliferation when conditions become abnormal. Here, cells are seen to “talk” with each other that help in a procedure called contact inhibition. A defective TGF-b pathway is seen to promote malignancy as it cannot takes place in apoptosis in abnormal situations and cells continue to grow (4). Cancer cells have the power of evading TGF-b anti-proliferative effects that adds to the situation (16).
Another hallmark of cancer is avoiding immune destruction by the cancer cells. The human immune system has the responsibility of protecting the body faint pathogens and diseases. It also plays an important role in clearing the unhealthy and ailing cells of the body. Moreover, it also has the capability of recognizing the cancer cells and eliminates them accordingly. In the presence of cancer cells, the body cannot provide immunity to the system (5). The cancer cells easily avoid the immune destruction activities.
Another hallmark of cancer is enabling of replicative immortality. In case of normal cells, it is seen that cells are able to pass through only particular number of cell division cycles. This is called the replication potential. In normal cells, replication potential is limited mainly because of the presence of the either senescence or crisis with the crisis mainly ending the life of a cell. Cells usually undergo a number of cell division and then they remain alive without undergoing nay further division. This is called limited replicating potential. After a period of crisis, when time arrives, the cell dies its normal death (6). However, in case of cancer cells, limited replication potential is never reached and for this reason, the cells go through unlimited replication. Chromosome and telomeres play important role in limiting replicative potential. In normal cells, telomeric repeats shorten after each cell division. Therefore, the length of telomeric DNA dictates the number of cell division cycles. In crisis periods in normal cells, loss of protective ends takes place for which normal cells die. In case of cancer cells, telomerase enzyme is produced that adds telomeric repeats constantly. This, thereby result in constant cell division (7).
Another important hallmark of cancer is tumor-promoting inflammation. For many years, researchers used to state that inflammation is associated with development of cancer but there were no proper works to prove it. In the recent past years, they have understood many of the molecular mechanisms of inflammation that is resulting in formation of cancer cells. Cancer through inflammation are seen to be linked with pollutants, chronic infections, obesity, alcohol consumption, smoking and many others. Some of the players in such tumor promoting inflammation is stated (8). One of them is NF-κB, deregulation of which, is linked to auto-immune diseases and cancer as they can no more control and regulate the cytokines. Another factor is the IKK Beta. This is a negative regulator of transcription factor NF-κB for which the latter cannot control cytokines. Other tumor-associated macrophages are CD68, iNOS, CD163 and others. All their activities result in tumor promoting inflammation.
Another important hallmark is called the activation of invasion and metastasis. The cancers cells are seen to invade and thereby from distant metastasis. Most of the patients are seen to die from metastases rather than the primary cancers. There are a plethora of complex interactions and different regulatory pathways by which such phenomena takes place. Cancer cells are seen to modify their cell-matrix or cell-cell interactions that help them to pass through the first step of invasion and metastasis procedures (9). Cancer cells are seen to invade healthy tissues after which they enter in blood and lymphatic systems. Cancer cells are also seen to surpass the immune surveillance while moving though the blood circulation and lymphatic systems. Thereby, here, they show anchorage-independent-growth and survival. Cancer cells are then seen to undergo extravasations from the vessels and enter the target sites causing micrometastases that later form secondary tumor (10).
Another hallmark of cancer is the inducing angiogenesis. Cancer cells are seen to not only proliferate but also increase in size and mass. This proliferation of tumors would become limited if there is no supply of oxygen and nutrients. However, this does not occur mainly because the cancer cells undergoes a procedure of angiogenesis. By the procedure of angiogenesis, they would be able to get the capability of formation of new blood vessels. This procedure not only allows the tumor cells to get proper supply of nutrients and oxygen but also have many other advantages. They allow the tumors to dispose the different metabolic texts that are toxic and thereby the cells enter into the hematogenous metastatic process (11). Usually the procedures of vasculogeneis and angiogenesis are usually observed in embryonic development where they mainly gets restricted in the stage. However, under certain situations they are seen to be reactivated. An angiogenic switch is activated in the time of tumor progression that result in undisrupted sprouting of new blood vessel which maintain tumor progression.
Another important hallmark of cancer is the genome instability & mutation. Cancer cells show variations. They vary and compete and those which are the fittest are successful in surviving and thereby passing onto the genes to the daughter cells. These are also seen to compete, vary and survive. In other words, it is seen that the cancer cells go through a procedure of evolution. Cancer cells are seen to mutate within our bodies. They also are seen to face selective pressures. The evolving cancer cells have to make sure that they outcompete the different types of normal cells that are surrounding them, overcome the attack of the immune cells and thereby escape the apoptotic machinery which are responsible for cells to undergo self destruction (12). They should also co-opt and corrupt the normal surrounding cells and undergoes migration to different distant parts of the body. Under sequences of mutation, sequences of nucleotides in the genes are seen to mutate. It is miscopied although chances of such occurrence are very less. When such mutation increases the evolutionary fitness of the cells, they seem to undergo expansion into many cells. These increase the probability that subsequent mutations would be built on the first (13). Cancer mainly occurs due to the stepwise accumulation of mutation. When the cancer cells are seen to undergo mutation that helps it in growing faster or are helping them to survive longer and producing more offspring in comparison to that of the normal surrounding cells who are not having that mutation, the cancer cells are said to have selective advantage. Such of the descendants of the cancer cells will be fitter who will outgrow and thereby dominates the different local tissue environment.
The other hallmark would be resisting cell death. In normal cells, three types of cell deaths can take place. The first mechanism is apoptosis. This takes place when various internal and external stimuli result in death of cells in a controlled manner. Inductions of DNA damage by chemotherapic agents thereby help in triggering cell death by apoptosis via TP53. This pathway induces expression of Noxa and Puma. They are pro-apoptotic proteins that lead to cell death. In cancer cells, TP53 gene is lost which thereby result the cells from overcoming the procedures of apoptosis. Moreover, tumors also show an excessive expression of survival factors like BCL2 and BCL-xl. Therefore, apoptosis does not take place in cancer cells. A second mechanism of death in normal cells are autophagy by which cells disintegrates its organelles and use the disintegrated organelles to fuel the energy of the cells. Mice cells without critical factors for autophagy induction like Becline 1 gene shows absence of authophagy (14). Necrosis is another form of cells death that occurs in normal cells. However, such necrotic cells can do both activities – like elimination of cancer cells or even helps in promoting their expansion. They are able to attract pro-inflammatory cells. This can in turn result in angiogenesis and proliferation of cancer cells. They also result in invasion of the cancer cells.
The last hallmark is deregulating cellular energetic. Cancer cells are seen to be involved partly in altering and modifying different energy metabolism for supporting division of growth. In case of normal cells, in aerobic conditions, it is seen that glucose during glycolysis in the cytoplasm is converted to pyruvate. It is then converted to carbon dioxide in mitochondria. In case of anaerobic conditions, there is favoring of the glycolysis and in their case, very little amount of little pyruvate is dispatched to the oxygen- consuming mitochondria (15). However, in cancer cells, energy metabolism is different. They can take part in reprogramming of their glucose metabolism and hence can control their energy production. This can be done by limiting their energy metabolism largely to glycolysis. This leads to a state that is called glycolysis. This is mainly because of the abnormal activity of lactate dehydrogenase. In normal cells, LDH coverts pyruvate to lactate under conditions of no oxygen or low oxygen. In cancer cells, activity of LDH in increased irrespective of the oxygen supply (16) (Figure 3).
Activating invasion and metastasis- Tissue invasion refers to the extension of neighbouring tissues into cancer cells, succeeded by their penetration. Once the tumor cells become capable of penetrating adjacent tissues, activating invasion begins. This results in the passing of all motile cells through the extracellular matrix and basement membrane. The cells further progress to intravasation, while penetrating the vascular or lymphatic circulation. The metastatic cells then acquire the ability to move through the extensive circulatory system (17). This is followed by extravasation that is the process of leaving the bloodstream. Finally, the cells are found to adhere at new region or location, succeeded by their proliferation. This leads to the formation of secondary tumor (18) (Figure 4).
Several cytoskeletal modifications and changes in the adhesive properties of the cells have been found to regulate cell motility. A cell generally commences polarization and extends protrusions towards the direction in which it will migrate. This occurs due to leading edge extension that is governed by filopodia or lamellipodia protrusions (19). Tissue invasion is further facilitated by cell contraction, mediated via the contractile forces of actomyosin complex.
Taxane drugs such as, docataxel and paclitaxel have been found effective in treating metastatic breast cancer. These drugs belong to a class of anticancer agents that effectively bind to the microtubules, thereby stabilizing them. This results in arrest of the cell cycle and subsequent apoptosis or cell death (20). Research studies state that disruption of microtubule function is the principal mechanism of action of these classes of drugs (21). Evidences support the fact that these drugs play an essential role in stabilizing GDP-bound tubulin present in the microtubule, which in turn prevents depolymerisation. This has often been found to result in shrinkage of breast tumors, upon comparison with non-taxane chemotherapy (22). Similar findings have also been reported by implementation of taxane based chemotherapy in metastatic prostate cancer. According to research studies, combination of docetaxel with androgen deprivation showed enhancement in overall survival of the metastatic cells. Taxanes act in the form of mitotic inhibitors and exert their action as mitotic poisons. Findings indicate that centrosomal impairment blocks cell cycle progression and leads to the induction of abnormal spindle fibres (23). This further triggers apoptosis of the metastatic prostate cancer cells, by aberrant mitosis that has been induced by taxanes (24). Thus, taxane induced chemotherapy has been found effective in treatment of metastatic breast and prostate cancer.
Angiogenesis- It refers to the physiological process of formation of new blood vessels from the pre-existing ones. This process occurs throughout life. It begins in the utero and is found to continue until old age. Tissue invasion and metastasis have been found to depend on the process of lymphaniogenesis and angiogenesis, which in turn are triggered by the tumor cells. The process of neovascularisation or angiogenesis involves four steps (25). Firstly, there occurs injury of the basement membrane present in the tissues that have been injured locally. This results in hypoxia and immediate destruction. The step is followed by activation of the endothelial cells by migration of several angiogenic factors. The third step involves proliferation and stabilization of the endothelial cells. The step is succeeded by exertion of the influence of angiogenic factors (26) (Figure 5).
According to research studies, vascular endothelial cells are found to divide after every 1000 days. Findings further provide evidence for the fact that requirement of oxygen and nutrients trigger the process of angiogenesis. Plethoras of inhibitor and activator molecules are found to govern the process. Of the several activator proteins that have been identified imperative for the process, vascular endothelial growth factor (VEGF), angiogenin, basic fibroblast growth factor (bFGF), TGF-β, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)-α, and platelet-derived endothelial growth factor play the most important role (27). Evidences indicate that influence of growth factors and cytokines result in the appearance of VEGF in the cancerous cells and the surrounding stroma that results in neovascularisation. Furthermore, hypoxia has also been found to lead to the formation of several angiogenic phenotypes. The condition results in VEGF expression via the action of hypoxia-inducible factor-1α (HIF-1α) (28). The tumor cells are found to feed on the blood vessels by VEGF production. VEGF binding to the receptors result in activation of relay proteins that transmit signals to the endothelial cells and up-regulated production of endothelial growth factors.
Angiogenesis inhibitor drugs are found effective in preventing growth of new blood vessels. The common mechanism of action of the drugs includes the stoppage of blood vessel growth that prevents nourishment of the blood vessels, thereby halting metastasis (29). According to research findings, thrombospondins TSP-1 and TSP-2 are considered as potent endogenous angiogenesis inhibitors. They directly affect cell migration, proliferation, and survival of the endothelial cells. This action is triggered by exerting an antagonistic effect on VEGF (30). These effects of the drug are mediated by a wide range of signal transduction molecules and membrane receptors. Thrombospondin exerts the effect through integrins, CD36, and CD47. Moreover, recent studies also indicate that a collaboration between β1 integrins and CD36 helps in transmitting signals, initiated by the drug. It results in a crosstalk between pro- and antiangiogenic signal pathways that inhibits angiogenesis, through the activation of apoptotic pathways (31). Another potent angiogenic inhibitor drug is bevacizumab, a monoclonal antibody. It binds to the VEGF. Adhesion to VEGF prevents activation of the VEGF receptor (32). Findings also suggest that the adhesion downregulates the downstream signaling pathways. Therefore, the drug effectively prevents stimulation of angiogenesis, thereby preventing further spread of the tumor cells (33).
To conclude, hallmarks of cancer refer to ten distinct biological capabilities that result in tumor development. The aforementioned hallmarks form a logical principle based on which the diversity of neoplastic diseases are explained. Progression of normal cells to a neoplastic state, require acquisition of the ten hallmark capabilities. This is imperative in tumor pathogenesis. The hallmarks increase the capability of the cancer cells of becoming tumorigenic, following which they spread to different regions of the body, and become malignant. Thus, it can be concluded that there are a plethora of cell growth factors that are essential in these hallmarks. Hence, these factors act as major drug targets for cancer treatment.
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