Regulators of Invasion

Several growth factors have been identified as important paracrine regulators of cancer growth and spread. Chief among these are those that bind receptor tyrosine kinases, such as EGF, hepatocyte growth factor/scatter factor (HGF/SF), transforming growth factors, and platelet-derived growth factor. Elevated expression of EGF receptors (EGFRs) and related Erb-B receptors has been found in many human malignancies. In cancers of the breast, head and neck, urogenital tract, and other tissues, Erb-B receptor overexpression is associated with poor prognosis.70 The Erb-B2 receptor, also known as Her-2/neu, is of particular interest because of its ability to form cell surface heterodimers with other Erb-B family receptors, thus augmenting receptor tyrosine kinase signaling.71

Our initial interest in studying the role of EGF in thyroid cancer stemmed from the fact that EGF is highly expressed in the normal human thyroid, at levels more than twice those found in other major organs.72 Several groups, including our own, have identified Erb-B receptors on the surface of thyroid cancer cells, and we have found that thyroid cancer cell lines overexpress both the EGFR and Erb-B2 when compared with normal thyrocytes. As mentioned earlier, EGF is a potent stimulator of thyroid cancer cell invasion. In some cases, in vitro invasion by EGF-stimulated cells was found to be seven times greater than that of cells studied in a growth factor-free environment. In previous reports from our group, TSH was also shown to enhance invasion.73

Both EGF and HGF/SF have been shown to increase protease expression and invasion in human cancers.7475 Furthermore, they are reported to induce the dismantling of adherens junctions, possibly by disrupting the cadherin-catenin linkage to the actin cytoskeleton.46 Similar paracrine signals are known to regulate the epithelial-mesenchymal transformation during normal embryonal development, which mirrors the pathologic events of malignant progression in many ways. Thus, proteins that maintain normal epithelial cell architecture, such as E-cadherin and catenin, are now being seen as invasion or metastasis suppressors.

Stromal cells have been recognized as having an active role in both the progression and inhibition of malignant invasion. Stromal cells secrete a variety of proteases, and cancer cells may stimulate them to synthesize MMPs in a paracrine fashion by releasing growth factors and human extracellular matrix metalloproteinase inducer (EMMPRIN76). Coculture with activated stromal cells can confer a malignant phenotype on immortal cells that generally display benign behavior.77'78 On the other hand, tumor stroma has in many cases been found to harbor large quantities of protease inhibitors,79 suggesting that normal fibroblasts may mount an adaptive "tumoristatic" response.

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