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If heparanase is the answer, what is the question?

The question may well be: what is the mechanism by which low-molecular-weight heparin (LMWH) appears to prolong survival in patients with cancer? In each of six recently published randomized-controlled trials (RCTs), four different types of LMWH increased the survival in patients with advanced cancer [1–6]. In four of the six studies, survival was a primary endpoint [1–3,5], while prevention of thrombosis and bleeding was the primary endpoints in the other two studies; survival was a secondary endpoint [4,6]. It should be noted that in four of the studies [1,2,4,6] the investigators either did not specify the endpoint prospectively and/or were able to demonstrate the survival benefit only in a sub-population of patients analyzed retrospectively (e.g. those with limited disease or better prognosis). Nevertheless, these RCTs provide support for a hypothesis generated by the data from previously published meta-analyses, wherein 3-month survival in cancer patients treated briefly with LMWH was superior to matched cancer patients treated with unfractionated heparin (UFH) [7–11]. The favorable results in cancer patients [generally a subset of larger studies of treatment of patients with venous thromboembolism (VTE)] could not be demonstrated in noncancer patients in the same studies. Although VTE complicating cancer has an adverse effect on prognosis across all tumor types [12–16], death in these patients usually occurs because of cancer, not to VTE [13–15]. Indeed, rather than preventing fatal pulmonary emboli in cancer patients, it seems more likely that an LMWH has either direct effects on tumor growth and metastasis and/or indirect effects mediated by inhibition of thrombin generation, the latter of which has been widely implicated in the growth and metastasis of tumors [17]. Several interesting and possibly related mechanisms may be invoked to explain the beneficial effects of LMWH on cancer survival, including preferential effects on the release of tissue factor pathway inhibitor from the endothelium [18], direct inhibition of tumor selectins [19], or inhibition of the tumor microenvironment remodeling enzyme heparanase [20]. In regard to the latter mechanism, heparan sulfate proteoglycans (HSPGs) have been identified as essential for both normal and pathologic processes, including early embryogenesis, morphogenesis, tissue repair, neurite outgrowth, inflammation and autoimmunity, tumor growth and metastasis, vasculogenesis and angiogenesis. Vlodavsky and Friedmann, in a seminal review noted that... transmembrane HSPGs mediate cell interactions with components of the microenvironment that control cell shape, adhesion, proliferation, survival, and differentiation [20]. Thus, it is not surprising that ubiquitous HSPGs are capable of participating in such a variety of critical biological functions. Heparanase appears to be the predominant species of endoglycosidase responsible for cleaving HSPGs and, relevant to this discussion, is preferentially expressed in human tumors, including breast, colon, lung, prostate, ovary, and pancreatic carcinomas. Normal tissue from these organs (e.g. breast) express little or no heparanase, and the level of heparanase mRNA in some tumors has been shown to correlate significantly with survival (e.g. pancreatic carcinoma) [21]. Vlodavsky et al. [20], along with several other laboratories, cloned the mammalian heparanase gene and have extensively characterized the properties of this endoglycosidase. Transfection and overexpression of heparanase in some non-metastatic tumor cell lines converts them to metastatic behavior in experimental model systems, such as in T-cell lymphoma cells (Fig. 1) and in human myeloma cells. Increased heparanase expression induced spontaneous metastasis of the myeloma cells to bone [22]. In this issue of the Journal, Nasser et al. [23] from the Vlodavsky laboratory provide another chapter in this remarkable saga of the potential role of endogenous heparanase in the pathophysiology of malignancy. The authors demonstrate the ability of preparations of UFH and LMWH to serve as substrates for the enzymatic activity of cloned mammalian heparanase. They extrapolate from sizing exclusion chromatography and test tube neutralization experiments of the Correspondence: Frederick R. Rickles, Departments of Medicine, Pediatrics and Pharmacology and Physiology, The George Washington University, The Federation of American Societies for Experimental Biology, 9650 Rockville Pike, Bethesda, MD 208143998, USA. Tel.: +1 301 634 7090; fax: +1 301 634 7049; e-mail: frickles@faseb. org Journal of Thrombosis and Haemostasis, 4: 557–559