Biological and clinical relevance of Laminin-5 in cancer

The occurrence of metastases is the hallmark of cancer. Development of meta stasis severely affects prognosis and survival. It limits or discourages th erapeutic interventions since no therapies are available to block or preven t cancer invasion. In order to invade, epithelial cancer cells need to pene trate through the basement membrane (BM) and remove extra-cellular matrix ( ECM) tissue boundaries. In this context, proteases play a key role since th ey can either degrade or process the ECM components and thereby support can cer cell invasion. Laminin-5 (Ln-5) is an ECM protein, expressed predominan tly in the BM structure, that promotes static adhesion and hemidesmosome fo rmation. However, it also stimulates cell migration and/or invasion after h aving been cleaved by matrix metalloproteinases (MMPs) such as MMP-2 and MT 1-MMP. Based on its dual functions, it would be intriguing to elucidate the role that Ln-5 plays in cancer cell motility and metastasis. One possibili ty is that MMPs, secreted by cancer cells or by neighbouring stromal cells, can cleave the gamma2 chain of Ln-5 deposited along the advancing edge of tumors. Ln-5, and in particular its gamma2 chain, has been found to be pref erentially expressed in the cytoplasm of epithelial human cancer cells loca ted at the advancing edge of the tumor. Such a distribution, which is restr icted only to malignancies, suggests that the gamma2 chain may be implicate d in epithelial cancer growth and invasion. Although the clinical significa nce of this finding is not yet clear, it seems often to be associated with a more aggressive and invasive cancer phenotype. This article will review t he current body of evidence implicating the Ln-5 molecule, and in particula r its gamma2 chain, as an important player in the tumor cascade and progres sion to metastatic disease. This will then be followed by a discussion of t he presented data and its limitations. Finally, suggestions will be provide d to improve the current state of knowledge in the field and future implica tions will be briefly discussed.