Importance of Angiogenesis for the Development and Treatment of Cancer - Literature review Example

Importance of angiogenesis for the development and treatment of cancer Name of the Student: Name of the Instructor: Name of the course: Code of the course: Submission date: Abstract Extensive efforts have been experienced in the past in the treatment of cancer around the globe, with major investments being committed towards this course. This is based on the severity of cancer in contributing to increased mortality among populations in different parts of the world. Perhaps the major breakthrough in this venture was realized in the 1970s with the cognition of the core role of angiogenesis in the development, growth and spread of cancerous cells. Based on this realization, studies conducted revealed that curtailing the growth of blood vessels which are primary in supplying oxygen and nutrients to the tumors was primary in slowing the growth of these cancerous cells or completely stopping it. This resulted in the advent of anti-angiogenesis therapy which has evolved to become central to cancer treatment in the contemporary world. This approach is endowed with various strengths, for instance, limited side effects. Nonetheless, it also have some weaknesses which have been cited by those who opposed this approach, for instance, in terms of assessing the efficacy of the anti-angiogenic therapies. This field of study is important based on its contribution towards treatment of cancer, albeit being confronted by several challenges in the future. Keywords: Angiogenesis, Anti-angiogenesis therapy, Chemotherapy, Endothelial cells Introduction It is imperative to note that the formation of new blood vessels out of the ones which are already in existence, or what is commonly referred to as angiogenesis has been cited as being a series of events which is integral importance in a wide alley of pathologic and physiologic processes (Griffioen and Molema, 238). Nonetheless, Zetter (407) determined that despite the long time cognition of the fact that majority of the solid tumors in the body comprise of a massive number of blood vessels which are highly permeable, the fundamental role of these vessels in permitting the growth of tumors was generally unappreciated in the past decades. However, the importance of angiogenesis in the development and treatment of cancer has gained recent support from diverse scholars, for instance, Folkman (1995) and Hanahan and Folkman (1996) who have cited that cancer among other diseases have the potential of greatly benefiting from the therapeutic reticence of angiogenesis. Against this backdrop, this section will primarily focus on the importance of angiogenesis for the development and treatment of cancer among patients. Importance of angiogenesis for the development of cancer Angiogenesis has been determined to play a central role in the development of cancer. This is founded on the fact that there is usually no vascularization of solid tumors which are smaller than 1 to 2 cubic millimeters. Nonetheless, their eventual expansion and spread ought to be facilitated through the supply of blood vessels which are imperative in bringing in oxygen and nutrients as well as removing the metabolic wastes (Herte, 50). Thus, the success of development, expansion and spread of cancerous tumors is usually dependent on active angiogenesis (Gardlik, 428). Based on the fact that angiogenesis is a normal process in the course of growth and development (Tiwari, 1), the angiogenesis in a tumor has been cited as being central to the development, growth and spread of the cancerous cells. The following diagram shows the central role of angiogenesis in the development, growth and spread of cancer. Figure 1.0: Angiogenesis in the development, growth and spread of cancer Source: Zetter (419) Thus, the sustainability in angiogenesis in the patients’ bodies has been viewed as a hallmark of cancer (Hanan, 58) and as a result, diverse studies on the mechanisms through which cancerous tumors promote the formation of new blood vessels has evolved into becoming a realm of research which has been active in the last two decades (Tortora, Melisi and Ciardiello, 11). This possibility was key in triggering intensive search for the pro and anti-angiogenic molecules and in 1976, Gullino exhibited that cells which are located in the pre-cancerous tissues end up obtaining the angiogenic capacity as they progress into becoming cancerous. As a result, he proposed that the same concept can be put into utility in the efforts to design strategies for curtailing cancer, a hypothesis which was later endorsed by genetic approaches (Carmeliet and Jain, 249) This has led scholars like Skobe et. al (1997) to infer that it is evident in the contemporary world that angiogenesis is not only necessary in the growth of tumors, but it is also associated with the initial development from a pre-malignant lesion to a cancer which is fully invasive as well as in the growth of the dormant micrometastases into metastatic lesions which are clinically detectable. Members of the vascular endothelia growth factors (VEGF) as well as the angiopoietin (Ang) have been cited as playing a major role in the formation of the tumor vessels (Carmeliet and Jain, 249). It is imperative to note that the VEGF/VEGF-receptor axis comprises of multiple ligands as well as receptors with overlying and unique ligand-receptor binding cell-type expression and functioning (Hicklin and Ellis, 1011). Thus, the activation of the VEGF-receptor pathway prompts a maze of signaling processes which stimulate the growth of endothelial cells, migration and the survival of the vasculature which were in pre-existence. In addition, VEGF facilitates the permeability of the vessels and has widely been linked with malignant effusions (Hicklin and Ellis, 1011). On the other hand, recent studies have indicated that proteases are highly involved in the early tumor growth, both at the primary and metastatic sites. This is whereby the extracellular proteases might jointly influence matrix degradation as well as tumor cell invasion through proteolytic cascades, where the individual proteases have specific roles in the growth of the tumor, invasion, migration as well as angiogenesis (Koblinski et. al, 113). Lastly, Wong and Wang (65) determined that stromal interactions which are linked to angiogenesis are also central in cancer growth, for instance, in development of prostate cancer whereby these processes are not only primary in the growth, development and functional cytodifferentiation of the prostate but also in the disorganizations of prostate glands such as BPH and prostate carcinoma. Importance of angiogenesis for cancer treatment It is fundamental to restate the fact that anti-angiogenesis therapy is founded on the theory that blocking the formation of new blood vessels in the tumors will eventually culminate to the slow growth or completely stop its growth (Ebos and Kerbel, 210). The imperative role of gaining a comprehensive understanding of angiogenesis in the treatment of cancer has been as a result of the failure of previous interventions like chemotherapy whose limited success in the treatment of cancer is based on both the inherent and acquired drug resistance (Ledzewicz and Schattler, 1). Perhaps the limited efficiency of the chemotherapeutic agents is founded on the fact that they fail to particularly target the actual tumor cells and rather pose interference to the processes of cell division or restrain the enzymes which are involved in the replication of deoxyribonucleic acid (DNA) or metabolism (Wu, Huang and Chang, 37). In addition, MacDonald (1) determined that based on the fact that cancer cells are usually characterized by an extremely high rate of mutation (genetic instability), the constant and repeated exposure to chemotherapy often culminates in a massive population of residue tumor cells which have mutated to become resistant to chemotherapeutic effects. On the contrary, the rationale behind the importance of angiogenesis in the treatment of cancer is founded on the fact that since the normal cells are not usually prone to genetic instability which is evident in cancer tumors, then there is little likelihood of resistance to drugs which can affect their functions (MacDonald, 1). With this latter approach, oncologists are not obliged to limit their concentration to the individual cells which are cancerous but might also direct their attention towards the entire tissue environment as the potential therapeutic target during cancer treatment. It is imperative to note that the drugs which are usually designed to stop angiogenesis in tumors are referred to as angiogenesis inhibitors or anti-angiogenesis drugs (American Society of Clinic Oncology website, 1) Thus, more recent interventions have been geared towards combining angiogenesis inhibitors which are peculiar cancer-fighting agents as they tend to constrain the growth of the blood vessels as opposed to the tumor cells, with the latter approach being predominant in more conventional interventions like chemotherapy. In some cancers, National Cancer Institute (1) determined that the angiogenesis inhibitors are most effective when they are combined with supplementary therapies, especially chemo. According to the American Society of Clinic Oncology website (1), a dominant hypothesis has proposed that the combination of both of the above approaches is founded on the presumption that these drugs aid in normalizing the blood vessels which supply the tumor, and in turn facilitating the delivery of other anti-cancer agents like chemo, although this possibility is still under investigation. Therefore, decades of active investigation have resulted in anti-angiogenic agents finally reaching the clinics in different regions around the globe. This is best epitomized by the first of these drugs-bavacizumab which is FDA-approved and has been extensively approved for use in lung, breast, colon and kidney cancers as well as glioblastoma as evidenced in diverse literature, for instance, Hurwitz et, al (2004), Sandler et. Al (2006), Giantonio et. al, (2007), Miller et. al (2007) and Escudier et. al (2007) among others. The immediate functioning of Bavacizumab as an anti-angiogenesis drug is through binding and inactivating VEGF and subsequently constraining endothelial cell activation and proliferation. On top of inhibiting the flow of nutrients to the tumor, this VEGF inhibition by bavacizumab has been revealed to stimulate vascular normalization, restoration of normal structure, function and flow to the leaky vessels in the malignant tumors which are often disorganized. As a result, these changes are primary in the enhancement of oxygen and nutrients delivery as well as cytotoxic chemotherapy to the tumor (Eskander and Leslie, 1). More recently, aflibercept (VEGF Trap) which is combined with standard chemotherapy regimens has been undergoing phase ii and phase iii clinical trials aimed at providing a solution in the treatment of solid tumors which have progressed, most predominantly in five different cancers, namely colorectal cancer, prostate cancer, gastric cancer, pancreatic cancer and NSCLC (Feng et. al, 6). To date, anti-angiogenesis therapy has extensively been considered as being a promising approach in the treatment of cancer at the global level. This has resulted in this approach being perceived as supposedly leading to the discovery of the much needed breakthrough in cancer therapy among other proangiogenic diseases. This has been pointed out by scholars like Abdollahi and Folkman (2010). Strengths of anti-angiogenesis in cancer treatment There are some major strengths which are evident in the use of anti-angiogenesis drugs in the treatment of cancer as cited by the proponents of this approach, mostly in regard to drug resistance and well as limited side effects. Firstly, they have cited that based on the fact that endothelial cells have extended genetic stability, the anti-angiogenic agents are bound to have limited impact in causing resistance. Secondly, under the normal psychological circumstances, more than 99% of the endothelial cells have been cited as being quiescent (Wu, Huang and Chang, 40). Thirdly, the physiological angiogenesis has been found to be different from lymphangiogenesis and arteriogenesis and is prominent in reproduction, wound repair, development and growth factor pathways as epitomized in the work by Dekker, et al (2006). This has resulted to the proposition by scholars like Folkman (2004) that the endothelial cells which are tumor stimulated have a peculiar migrating and proliferating phenotype when they are juxtaposed with quiescent endothelial cells and thus targeting this phenotype would be so precise that there would be limited occurrence of major side effects. Nonetheless, despite these strengths, there are some weaknesses which have been cited by different weaknesses which have been pointed out by some individuals and collectives who are against this approach to cancer treatment. This is exemplified in the subsequent analysis. Weaknesses of anti-angiogenesis in cancer treatment Firstly, Fischer and Carmeliet (4) determined that the mechanism of assessing the efficacy of the anti-angiogenic therapies still remain to be established, whether the administration of a singular angiogenic molecule is endowed with any sufficiency and whether the anti-angiogenic treatment on the long-term basis has the overall effect of causing delayed toxicity. Secondly, it is yet to be established whether the sensational effects of this approach which have been realized in preclinical investigations where xenogeneic and syngeneic tumor transplant models and transgenic systems are also prevalent in human situations (Griffioen and Molema, 238). Lastly, O’Reilly et. al in their works in 1994 and 1997 cited that it has been revealed that the angiogenesis inhibitors, angiostatin and endostatin to not cause resistance which is drug induced on prolonged treatment among tumor-bearing animals, albeit being highly effective in the reduction of tumor growth Nonetheless, it remains vague on whether this scenario is replicable among other angiogenesis inhibitors as well as other proangiogenic diseases which have elicited increased interest in the recent past. Conclusion From the above review, it is apparent that anti-angiogenesis therapy is based on the concept that blocking the formation of new blood vessels in the tumors will eventually culminate to the slow growth or completely stop its growth. The use of anti-angiogenesis therapy in the treatment of cancer has extensively been considered as being a promising approach in the treatment of cancer in different regions of the world. The importance of angiogenesis in the development of cancer is founded on the fact that the development of new blood vessels which are central in supplying oxygen and nutrients and removal of wastes from the cancerous cells are integral to their growth and spread. Thus, anti-angiogenesis therapy is fundamental in the treatment of cancer in the sense that it constrains the growth of blood vessels into the tissues containing cancerous cells and thus slows down or absolutely stops the growth of the tumor. Nonetheless, this latter process has some strengths as well as weaknesses which were analyzed in the preceding section.  Importance of this field/topic and the major challenges for the future This field of study is imperative based on its central role in advancing knowledge in the treatment of cancer in different parts of the world. This is against the background that cancer was estimated to account for approximately 7 million deaths (12%) of all the deaths in the world in year 2000 (Mathers et. al, 2001). This shows the great importance of fortifying the old ways as well as seeking new approaches in the treatment of cancer in the contemporary world, which is central to this topic. Nonetheless, there are bound to be several challenges in the future, mostly the affordability of these services in among the developing and least developed countries as well as the present lack of validated predictive biomarkers to stratify the cancer patients and to monitor the progression and response of the tumor (Shojaei, 130). This calls for immediate interventions to counter these problems (Kerbel, 512) to ensure that cancer patients get utmost care (Hurwitz, 1). Works cited Abdollahi, A. and Folkman, J. Evading tumor evasion: current concepts and perspectives of anti‑ angiogenic cancer therapy. 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