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Growing cells are located within defined environmental niches and any area outside the niche is very hostile. Because normal cells lack survival techniques, it leads to anoikis. The tumor development process strives when malignant cells escape from the local issues and resist anoikis. The cells of the immune system play a dual role of stimulating adaptive immune responses against tumor-specific antigens and at the same time promoting tumor angiogenesis and progression. This is through the support of the innate and inflammatory responses (Ravi et al., 2000).
Integrins are termed as a family of adhesion receptors or heterodimeric transmembrane glycoproteins that assigns cells to extracellular matrix proteins of the cellar membrane or the ligands on other cells. It contains large alpha and small beta subunits ranging from 120 to 170 kDa and 90 to 100 kDa consecutively. Some integrins arbitrate direct cell to cell interaction and recognition. Integrins contain binding sites with Magnesium or Calcium ions necessary for their adhesive nature. A characteristic feature of most integrins is their ability to bind a wide variety of ligands. In addition, the numerous matrix and cell surface adhesiomn proteins are able to bind to multiple integrin receptors (Bao et al., 2006).
β2 are totally expressed on leukocytes and undergo a conformational change that takes the phosphorylation of the beta subunit. A structure of the β2 integrin encompasses four different heterodimers CD11a/CD18- lymphocyte function associated antigen and is the predominant integrin, CD11b/CD18- exclusive to monocytes and granulocytes, CD11d/CD18, and CD11c/CD18. The most essential member of the β2 integrin is the Very Late Antigen-4 also represented as VLA-4, CD49d/CD29, α4 β1 which binds to the ligand VCAM-1 and is majorly responsible for lymphocyte adhesion to vascular endothelium and leukocyte conscription to the inflamed part. The structure of β2 integrin is as shown
Angiogenesis is the process of formation of tumor-associated vasculature and is as a result of stromal reaction necessary for tumor progression. The vessels associated with tumors promote the growth by providing the necessary conditions for growth. They provide nutrients and oxygen required for tumor metastasis and facilitate tumor cell entry into the circulation. Moreover, tumor-associated lymphatics facilitate the spread of tumor cells to the lymphatic nodes. The same happens with the tumor infiltration of the inflammatory cells which is facilitates progression and metastasis (Bao et al., 2006).
According to recent discovery, VEGF-C, VEGF-D and VEGF-R3 facilitate lymphatic vessel formation process otherwise regarded as lymphangiogenesis and this has boosted the study and research. VEGF-C, VEGF-D expressed by the tumor cells induces lymphatic vessel formation at the base and inside the tumors thereby increasing metastatic spread at draining locations such as lymph nodes and distant organs (Carmeliet, & Jain, 2000,).
Integrins has been found as preclinical and clinical evidence for therapeutic targets. In preclinical context, pharmacological inhibition of integrin carries out efficient angiogenesis and alters tumor progression. AlphaVbeta3 and alphaVbeta5 are the first integrins meant to suppress tumor angiogenesis. Further experiments on the field has revealed that four different integrins including alpha1beta1, alpha2beta1, alpha5beta1 and alpha6beta4 qualify as potential therapeutic targets (Plate, Breier, Weich, & Risau, 1992).
In the clinical context, it is found that clinical low molecular weight integrin inhibitors and antibodies such as antiintegrin function-blocking types show low levels of toxicity and better tolerability. They are currently tested with radiotherapy and chemotherapy sessions to provide anticancer activities in patients (Weidner, Semple, Welch, & Folkman, 1991).
The alpha-v integrin family is made of five groups namely; αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8 and are the most researched because they are believed to be better regulators of angiogenesis than the rest. Disparities are recorded due to the discordance between the pharmacological (antibodies, peptides and small molecules) and genetic (human mutation) research studies. This is because αIIbβ3 is an excellent target for antithrombotic drugs and if the same idea can be applied to αV that forms effective antiangiogenesis (Anderson, & Chaplain, 1998).
The figure shows the integrin family of adhesion receptors and the main ligands. It comprises of 18 alpha and 8 beta mammalian subunits that combine to form 24 diverse heterodimers. Integrins forms the main receptors for ECM proteins but can also bind soluble molecules, pathogens such as viruses and cellular counter receptors. The a6b1 integrin is associated with the LM and CCN1 ECM ligands and is characteristically lethal at birth for vascular phenotypes by constitutive gene elimination in mice. The suppression of tumor angiogenesis by pharmacological inhibitors is not absolute and research is ongoing.
The proposed structure of the integrins with head region and two legs is represented in the structure shown in figure. The head is comprised of a beat propelled alpha subunit and a propeller-like beta subunit domain. An interface between in between the two domains allow for staple association with the heterodimer. The legs are comprised of a rigid like stalk that has flexible hinge joints. The five cation binding sites are situated around the head while the sixth one is located at the alpha subunit near in the hinge region. T he alpha and beta cytoplasmic domains associatein a manner that leaves the integrin in a resting state.
Activation is triggered by the Talin binding to the beta cytoplasmic domain that disrupts the beta-alpha interaction thereby causing the ligand inside-out conformational alteration. Thus activation is characterized by movements of the beta and alpha stalks, unbending and transition of the ligand binding pockets to result in a high-affinity conformation.
Blood vessels are comprised of the endothelial cells forming the inner vessels and the pericytes or the mural cells that makes up the surface of the vascular tube. Pericytes are important because they form the functional and essential contributors to tumor angiogenesis process thereby necessary for angiogenetic therapy.
Pericytes exchibit a number of functions ranging from stabilization and hemodynamic blood processes to angiogenic stimuli, elicit endothelial survival functions and macrophage functions. In terms of angiogenesis, they have an active role in blood vessel formation. Endothelial cells and hematopoitic cells both posses a common precursor known as hemangioblast. Pericytes develop using complex ontogeny from various cells such as forebrain and neurocrest. Thus TGF-β1 develops differentiation of PDGFRβ+ pericyte progenitor cells which are then attracted to PDGF-B-secreting endothelial cells found in the capillary plexus. Similarly, pericytes is reported to be generated from TGF-β1 endothelial differentiation.
The assembling of the capillary cells triggers the angiogennic refinement into functional networks. The process describes the extensive sprouting and pruning of the vessels and angiogenesis may include endotheliai intussusception and cell bridging. In cell sprouting, angiogenic factors such as VEGF stimulate endothelial cells to secrete different proteases that degrade the vessel basement membrane. Endothelial cells will invade the surrounding ECM and develop a migration column that is purely comprised of proliferating and migrating endothelial cells. An example is the corpus lutuem in which the pericytes can guide the sproutingby migrating ahead of the endothelial cells and expressing the VEGF.
References
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