Role of angiogenesis in cancer pdf

When the tumor cells encounter endothelial cells, they bind to receptors on the outer surface of the endothelial cell. The binding of VEGF to its receptor activates relay proteins that transmit a signal into the nucleus of the endothelial cell. The nuclear signal prompts a group of genes to make products needed for new endothelial cell growth.

Abbreviations: AT1, angiotensin-1; AT2, angiotensin The MMPs break down the extracellular matrix which fills the spaces between cells and is made of protein and polysaccharides. This matrix permits the migration of endothelial cells. The endothelial cells begin to divide as they migrate into the surrounding tissues.

Newly formed blood vessels need to stabilize or mature. Angiotensin-1, -2, and their receptor Tie-2 can stabilize and govern vascular growth Suri et al ; Maisonpierre et al ; Tournaire et al Vascular endothelial growth factor-A is a heparin-binding glycoprotein that occurs in at least six molecular isoforms, which consist of , , , , , and amino acids and are the result of alternative splicing of the mRNA Ferrara et al ; Ferrara ; Stalmans et al VEGF-A is a potent and very specific mitogen for vascular endothelial cells and stimulates the full cascade of events required for angiogenesis Leung et al ; Conn et al , and is overexpressed in a variety of tumors Dvorak While VEGF-B is widely expressed in heart, skeletal muscle, and vascular cells Olofsson et al ; Yonekura et al , its biological function remains unclear.

It has also been reported that VEGF-B levels increase both throughout development and after birth, closely correlating with the progression of cardiac angiogenesis Bellomo et al The expression of VEGF-C appears to be restricted to early development and certain pathological settings such as tumor angiogenesis and lymphangiogenesis Peeper Up-regulation of the activity of angiogenic factors is in itself not enough to initiate blood vessel growth, and the functions of negative regulators or inhibitors of vessel growth may need to be down-regulated.

There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 Table 1. Angiostatin is composed of one or more fragments of plasminogen Stack et al It induces apoptosis in endothelial cells and tumor cells, and inhibits migration and the formation of tubules in endothelial cells Claesson-Welch et al ; Lucas et al Several studies have indicated that angiogenic activators play an important part in the growth and spread of tumors.

On immunohistochemical examination, the VEGF family and their receptors were found to be expressed in about half of the human cancers investigated Salven et al These factors are known to affect the prognosis of adenocarcinomas that have developed in the uterine cervix, Hashimoto et al , endometrium, Hirai et al , ovary Boocock et al ; Yokoyama et al ; Nishida et al , and stomach Yonemura et al ; Amioka et al In addition, a significant correlation between the expression of VEGF and prognosis has been described in colorectal cancer Andre et al ; George et al ; Furudoi et al , breast cancer Kurebayashi et al ; Gunningham et al ; Kinoshita et al ; Skobe et al , lung cancer Decaussin et al ; Niki et al ; Kajita et al , head and neck squamous cell carcinoma O-charoenrat et al , Kaposi sarcoma Jussila et al , and malignant mesothelioma Ohta et al These studies also indicated that the levels of angiogenic factors in tissue reflect the aggressiveness with which tumor cells spread, and thus have predictive value in the identification of the high-risk patients with poor prognosis.

Neovascularization reduces a tumor's accessibility to chemotherapeutic drugs. Increased interstitial pressure from leaky vessels in the tumor, in the relative absence of intratumoral lymphatic vessels, causes vascular compression and central necrosis Folkman b.

So it is not surprising that the prognostic value of neoplastic angiogenic factors is controversial. For some localized solid malignant tumors, surgery has curative potential, but the use of radiation and cytotoxic chemotherapy is a more appropriate route of treatment for surgically unresectable tumors Kim et al ; Long ; Brenner et al ; Pfister et al ; Lin and Beerm ; Awada and de Castro ; Evans ; Goldberg Despite advances in both therapeutic modalities, treatment results are disappointing in patients with advanced disease Jemal et al A new therapeutic strategy is urgently required.

The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of angiogenesis. This signaling activates certain genes in the host tissue that make proteins which encourage the growth of blood vessels Majima et al ; Semenza Cancer cells require access to blood vessels for growth and metastasis.

The discovery of angiogenic inhibitors provides hope for reducing the mortality and morbidity from carcinomas. Five classes of angiogenic antagonists are currently in clinical trials: inhibitors of proteases inhibit the synthesis of MMP ; endothelial cell migration and proliferation; angiogenic growth factors; matrix proteins on the endothelial cell surface such as integrins, copper; and inhibitors with unique mechanisms.

There has been a modest positive outcome with the use of antiangiogenic drugs based on some clinical trials Cobleigh et al ; Yang et al , but no long-term survival benefits have been documented as yet Mayer However, when used in combination with chemotherapy or radiation therapy, these drugs tend to increase survival Hurwiz et al Evidence seems to support the view that cytotoxic agents and antiangiogenic agents would destroy both cancer cells and endothelial cells Teicher Cytotoxic therapy suppresses cancer directly and angiogenic therapy suppresses it indirectly by depriving cells of nutrients and oxygen Rakesh The use of angiogenesis-suppressors and receptor-inhibitors can prohibit the neovascularization of cancer tissue as well as growth of the tumor, and thus might be beneficial to the treatment of cancer.

Paradoxically, some studies have shown that antiangiogenic agents as well as radiation can compromise the delivery of drugs to tumors Ma et al The new vasculature is structurally and functionally abnormal Jain , and the blood vessels are immature and leaky Tong et al Unlike normal blood vessels: 1 tumor vessels have no or a detached pericyte and basement membrane Inai et al ; Tong et al ; Winkler et al ; 2 the diameter of the vessel is smaller Yuan et al ; Izumi et al ; Tong et al ; Winkler et al ; 3 the vascular density is heterogeneous Izumi et al ; Tong et al ; Winkler et al ; 4 permeability to large molecules is high Yuan et al ; Tong et al ; Willett et al ; Winkler et al ; and 5 the pressure of microvascular and interstitial fluid is almost the same Lee et al ; Tong et al ; Willet et al These abnormalities contribute to heterogeneity in tumor blood flow.

In addition, the pressure generated by proliferating cancer cells compresses intratumoral blood and lymphatic vessels and leads to an abnormal microenvironment characterized by an impaired blood supply, interstitial hypertension, hypoxia, and acidosis Padera et al It is possible that these factors interfere with the delivery of therapeutic drugs, rendering tumor cells resistant to both radiation and some forms of cytotoxic therapy, induce genetic stability and select for more malignant cells with increased metastatic potential, and compromise the cytotoxic functions of immune cells.

Hence, Rakesh emphasizes that the tumor vasculature should be normalized. Some trials based on normalization of tumor vasculature have started, however, data are not currently available. There is a report that normalization can be achieved by controlling the dose of an already existing medicine, for example, low-dose anti-VEGF treatment. In the meantime, cancerous tissue is composed of the neoplastic cells themselves and the supporting stroma.

National Center for Biotechnology Information , U. Vasc Health Risk Manag. Published online Sep. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products.

Keywords: angiogenesis, immunohistochemistry, prognosis. Introduction Cancer has the ability to spread to adjacent or distant organs, which makes it life threatening. Angiogenesis in cancer Tumor growth and metastasis depend on angiogenesis and lymphangiogenesis triggered by chemical signals from tumor cells in a phase of rapid growth Folkman Open in a separate window.

Figure 1. Table 1 Endogenous regulators of angiogenesis. Inhibitors of angiogenesis Up-regulation of the activity of angiogenic factors is in itself not enough to initiate blood vessel growth, and the functions of negative regulators or inhibitors of vessel growth may need to be down-regulated.

Angiogenesis and the prognosis of cancer Several studies have indicated that angiogenic activators play an important part in the growth and spread of tumors. Antiangiogenic treatment of cancer For some localized solid malignant tumors, surgery has curative potential, but the use of radiation and cytotoxic chemotherapy is a more appropriate route of treatment for surgically unresectable tumors Kim et al ; Long ; Brenner et al ; Pfister et al ; Lin and Beerm ; Awada and de Castro ; Evans ; Goldberg Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa.

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This is a preview of subscription content, access via your institution. Rent this article via DeepDyve. You can also search for this author in PubMed Google Scholar. Correspondence to A. Reprints and Permissions. Hall, A. The role of angiogenesis in cancer. Comp Clin Path 13, 95—99