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The paracrine effect of VEGF is mediated via transmembrane receptors that are only present on endothelial cells, so VEGF is only mitogenic at this site; FGF receptors have a wider distribution. VEGF and FGF have synergistic effects on endothelial cells. VEGF receptors are typisine kinase receptors in that they require dimerisation, tyrosine phosphorylation of the domain and recruitment of SH domain protains (Chapter 11); recruited protains include phospholipase C, GAP and phosphatidylinositol_3_kinase, each capable of transducing the proliferative signal to the endothelial cell nucleus (Figure 12.9 and Chapter11). The VEGF receptor gene also contain an HIF response element and is activated by hypoxia. in addition to these prolifeerative effects, VEGF also promotes the secretion of serine proteinases and metalloproteinases as well as inducing integrins, VCAM and ICAM, all of which facilitate capillary sprout invasion of the ECM.
Several polypeptide inhibitors of angiogenesis have been identfied, e.g. angiostatin, endostatin and thrombospondin. the thrombospondin gene is activated by p53 (Figure 6.13) and this helps to block angiogenesis; mutant p53 dose not have this effect. Angiostatin and endostatin are partial proteolytic products of plasminogen and collagen XVⅢ respectively; they may act by binding to and blocking growth factor receptors need for endothelial proliferation. In a normal cell mass the blance of inhibitors and activators favours inhibition; cancers shift this blance to favour activation (Figure 12.10).
Invasion of the ECM is mediated in part by serine proteases and metalloproteinases secreted at the leading edge of the sprout in response to VEGF. Migration towards the cancer also involves attachment to the remodelled ECM, helped by the altered profile of endothelial integrins. the upregulation of ανβ3 by VEGF helps bececause the borad ligand specificity of this ontegrin enables interaction between endothelial sprout and diverse types of ECM (Chapter 11). As these interactions are needed for cell migration (Box 11.1), cell migration is enhanced by ανβ3 expression‎. And angiogenic growth factor FGF induces integrin, ανβ5.
Angiogensis involves more than proliferation and proteolysis. Capillary sprouts extend out towards the source of angiogenic stimuli, such as a clump of tumour cell, so chemotaxis os also important. The molecules involved in its regulation must reflect this fact, so it is not surprising that fibroblast growth faxtor (FGF), a potent angiogenic factor, can stimulate all three of the required propeties: proliferation, protease secretion and chemotaxis of endothelial cells.
The maturation and differrentiation phase of angiogenesis includes processes that determine the direction of blood flow. Smooth muscle cells are recruited to capillaries destined to become afferent arterioles but not those destined to become efferent venules. Little is known about the underlying mechanisms involved in adult life, but in embryos the boundary between theses two types of vessel is marked by differntial expression‎ of proteins. At the junction, the potential arterial endothelial cell expresses a transmembrane ligand(an ephrin) that interaxts with an ephrin tyrosine kinase receptor (Toe) only present on the adjacent venuys endothelial cell. These proteins may play an as yet indeterminate role in angiogenesis linked to metastaticspread of cancer.
Now that the basic features og angiogenesis are known, attention is being focussed on their manipulation for therapeutic purposes. Avenues of investigation include blocking ανβ3 integrins with neutralising antibodies, inhibiting MMPs with synthetic peptides and increasing levels of inhibitors like endostatin (Chapter 13). some of the components associated with angigenesis can also help to determine subsequent behaviour of a cancer at the time it is first detected(prognistic use). Antibodies against several of the proteins can be used as histochemical stains to identify vessels in tissue sections. A high vessel density correlates with poor survival in breast and prostate cancers, and sometimes the angiogenic switch (appearance of new capillaries) can be seen microscopically before the invasive cancer is evident. Thus, in cervical carcinogenesis, angiogenesis begins in the preinvasive CIN Ⅱ-Ⅲ stages (Chapter 2) before invasion begins. This fits with the view that angiogenesis is a rate-limiting event in cancer formation at the primary stage as well as during metastasis(discussed here).





Gnen changes involved in metastasis

Many gene products that influence metastatic spread have been mentioned in the preceding sections of this chapter. An important point to note is that different pathways are utilised by different cancers so there is no gene change that is common to all cancers. A caveat to this generalisation isthat the gene products involved in angiogenesis are common to all cancers.
Both oncogenes and repressors are involved in metastasis, some of which have been implicated in other aspects of cancer biology. Thus, ras activation is associated with increased proliferation and is an early event in colon carcinogenesis. Ras-transfected cells have increased metastatic potential. Other oncogenes such as v-src and v-raf can also increase proliferation, tumorigenicity(transformation in culture) and invasiveness. Although properties such as transformation and proliferation are essential for metastasis, the following experiment shows how they can be separated. Experimentally, ras transforms some cells without affecting metastasis, whilst viruses such as adenovirus can block metastastic properties of ras but not its transforming effect. This indicates that transformation and metastasis can be divorced and metastasis is not simply a consequence of early events in carcinogenesis and proliferation. It is not clear how changes in a gene such as ras can influence transformation in some situations and metastasis in others. As ras is a focal point for multiple upstream and downstream signal pathways (Chapter 10), it is possible that different responses are modulated in different cells.
The additional gene changes required for metastasis are poorly defined. Genes involved in angiogenesis, protease production and cell adhesion molecules are clearly important but others have yat to be characterised. fusion of metastatic mouse melanoma cells with normal cells can produce non-metastatic hybrids, which indicates that normal cells contain something that inhibits metastasis. Several putative metastasis-repressing genes have been identified. One such gene is nm23(non-metastatic protein23), which has clinical relevance in that its loss is correlated with increased metastasis in some tumours, e.g. liver tumours. However, nm23 changes do not occur in all tumours and it is actually increased in cancers such as ovary. The function of nm23 is obscure. It has nucleoside diphosphate kinase activity but this can be blocked without effect on its metastasis-inhibiting properties. The mammalian nm23 gene has a homologue in fruit flies, AWD, that is required for wing and eye development, so cell-cell interaction and differentiation may be involved.
The cell adhesion molecule CD44 may be linked to metastatic spread. Expression‎ of normal CD44 is decreased in metastatic colon and breast cancers whereas variant CD44s present a confusing picture - increased in some cases and decreased in others(Chapter 11).




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