Involved in Metastasis

As described earlier, the formation of metastases is a multistep event. Each of the different steps requires the production of different group of molecules. These molecules may be synthesised either by the metastatic cells, or by host cells collaborating with the metastasizing cells. Some of the key molecules involved in the metastatic process are now discussed. 

One of the key early events in the progression of cancer is angiogenesis or formation of new blood vessels. Without the formation of their own vasculature, 

During invasion and metastasis, malignant cells cross basement membranes at least three times. They first pass through these membranes during their escape from the primary site. Subsequently, the cancer cells invade basement membranes during both entry into and exit from the blood stream. 

Unlike the acellular basement membranes, the interstitial connective tissue consists of cells distributed in meshwork of collagen fibers, glycoproteins (e.g., fibronectin), proteoglycans, and hyaluronic acid. The main forms of collagen found in interstitial connective tissue are known as type I, II, and III or interstitial collagen. 

Degradation of these natural barriers by invading cancer cells is believed to be brought about by the release of a number of different proteases from the invading tumor. The proteases implicated in degradation of the extracellular matrix include the urokinase form of plasminogen activator (uPA), cathepsin B (CB), cathepsin D (CD), and various metalloproteases. These proteases appear to act in a cascade manner (Fig. 2) (S2). A brief description of the main proteases involved in metastasis now follows. 

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Proteases might also indirectly mediate cancer spread by either activating positive growth factors or inactivating suppressors of metastasis. One of the best examples of a growth factor activated by a protease is beta-TGF by plasmin (L3). There is, however, no evidence at present that beta-TGF is involved in metastasis. 

In recent years, a large number of new biochemical prognostic markers have been described for cancer. These include steroid receptors, cellular or c-onco-genes, suppressor genes, and molecules directly involved in metastasis, such as proteases and adhesion proteins. 

Carbohydrate-mediated cell adhesion is an important event which can be initiated by tissue injury or infection and is involved in metastasis. One such adhesion process is the interaction between the glycoprotein E-selectin and oligosaccharides on the surface of neutrophils (white blood cells). The ligand that E-selectin recognizes is the tetrasaccharide sialyl Lewis X (SLe ). Since SLe competes with white blood cells for binding to E-selectin, thus inhibiting the adhesion process, it may useful as an anti-inflammatoiy and anticancer agent. 

Many other proteins have been implicated in the genetic response to hypoxia, among them nuclear factor kB (NF-kB), activator protein-1 (AP-1 see Fig. 4.13b), and members of the unfolded protein response (e.g., GRP78). Their exact role in hypoxia-induced tumor progression is less clear. For example, hypoxic induction of NF-kB is likely to be the consequence of reoxygenation-induced reactive oxygen species. Overexpression of osteopontin (OPN) has been demonstrated to be involved in metastasis formation. OPN is overexpressed during hypoxia, and the transcriptional control seems to be independent of HIF-la. 

A large number of mammalian cells express sugar-binding proteins known as lectins. These have been found to be overexpressed on malignant cells and are believed to be involved in metastasis formation [31, 43] they can thus serve as a... 

The final chapter is dedicated to the state-of-the-art methods for determining lectin affinity and specificity for oligosaccharides. These play a key role in many biological processes relevant to cell communication and disease states, and are involved in cancer development and metastasis, inflammation and host-pathogen recognition. 

Since certain proteases are directly involved in cancer invasion and metastasis, levels of these proteases in primary cancers should be strong markers of metastatic potential or poor patient outcome. 

About 10-20% of all transmembrane proteins that are targeted to the ER and subsequently enter the secretory pathway are subject to post-translational modification with glycosylphosphatidyl-inositol (GPI). Proteins bearing the GPI anchor are involved in signal transduction, immune response, cancer cell invasion, and metastasis and the pathobiology of trypanosomal parasites. The structure of the GPI anchor has been analyzed for mammals, protozoa, and yeast. The general structure of the glycolipid structure is shown in Scheme 4. 

Osada T, Sakamoto M, Ino Y, Iwamatsu A, Matsuno Y, Muto T et al (1996). E-cadherin is involved in the intrahepatic metastasis of hepatocellular carcinoma. Hepatology 24 1460-1467. 

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