Morphogenesis and Differentiation Program
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Is a cure for cancer within reach?
Research in mice has shown that over-expression of the serine protease, matriptase, single-handed causes tumors with high efficiency . Matriptase is located on the basolateral plasma membrane of all epithelial cells [2,3] and all epithelial cell derived cancers , and catalyzes the conversion of signal molecules, leading to the activation of signal transduction pathways [5,6]. Matriptase is kept under strict control by HAI-1 and HAI-2 under normal conditions [7,8]. In contrast, seventy percent of mice overexpressing matriptase in the skin developed squamous cell carcinomas, whereas mice overexpressing both matriptase and either HAI-1  or HAI-2  had a malignant cancer incidence resembling wild type mice. Similar results were obtained from another mouse study, where the tumorigenicity and metastatic capability of human prostate cancer cells were studied . It was shown that the expression of HAI-2 diminishes during prostate cancer progression and furthermore that the tumorigenicity and metastatic capability of the prostate cancer cells was reduced, when HAI-2 expression was increased . Whereas, the way by which HAI-1 and HAI-2 control matriptase remains unclear, it clearly demonstrates that HAI-1 and HAI-2 are able to control the potent oncogenic potential of matriptase.
Even more importantly, mice with already established tumors, caused by up-regulation of the matriptase expression and application of a carcinogen to the skin, showed a markedly impaired malignant progression and regression of individual tumors upon the induction of HAI-2 expression . This suggests that HAI-2 and possibly also HAI-1 may provide a way to cure cancer if supplied at the right time and place.
Matriptase, prostasin (the non-enzymatic co-activator of matriptase ), HAI-1 and HAI-2 are all synthesized on the rough endoplasmic reticulum. Matriptase , prostasin  and HAI-1  are transported along the secretory pathway to the plasma membrane , whereas HAI-2 is a resident endoplasmic reticulum-protein . Based on this it is our hypothesis that the anti-oncogenic action of HAI-1 and HAI-2 takes place in the endoplasmic reticulum since this is the only subcellular localization shared between HAI-1 and HAI-2. Furthermore, based on the homology between HAI-1 and HAI-2  and redundancy in functions [16,17], we also expect the anti-oncogenic feature to be shared by the two.
The goal of the Vogel laboratory is to provide a basic understanding of the interplay between matriptase, prostasin, HAI-1 and HAI-2 in order to use this knowledge to design treatment(s) for cancer patients.
Thomas H. Bugge, NIH, Bethesda, Maryland, USA Chen-Yong Lin, University of Maryland, Maryland, USA Makiko Kawaguchi, University of Miyazaki, Miyazaki, Japan Hiroaki Kataoka, University of Miyazaki, Miyazaki, Japan Jan K. Jensen, University of Aarhus, Aarhus, Denmark Lars Ellgaard, University of Copenhagen, Copenhagen, Denmark