Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity.

Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and the glycocalyx, thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of the dual functions of HPSE to malignant melanoma in vitro, as well as in different mouse melanoma models based on the intradermal or intravenous injection of melanoma cells. Consistent with its extracellular action, an HPSE deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of vascular endothelial growth factor, affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently, MMP-9, upon HPSE knockdown. In vivo, an HPSE deficiency was related to increased lymph node metastasis. Since the inhibition of its extracellular function with heparin was unable to block the gene regulatory impact of HPSE, we proposed an intracellular mechanism. Immunostaining revealed a counter-staining of HPSE and NF-κB in the nucleus, suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual function for HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor-suppressive nuclear action. The identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells could provide new therapeutic options.

Inflammatory chemokines and metastasis--tracing the accessory.

The tumor microenvironment consists of stromal cells and leukocytes that contribute to cancer progression. Cross-talk between tumor cells and their microenvironment is facilitated by a variety of soluble factors, including growth factors and cytokines such as chemokines. Due to a wide expression of chemokine receptors on cells in the tumor microenvironment, including tumor cells, chemokines affect various processes such as leukocyte recruitment, angiogenesis, tumor cell survival, tumor cell adhesion, proliferation, vascular permeability, immune suppression, invasion and metastasis. Inflammatory chemokines are instrumental players in cancer-related inflammation and significantly contribute to numerous steps during metastasis. Recruitment of myeloid-derived cells to metastatic sites is mainly mediated by the inflammatory chemokines CCL2 and CCL5. Tumor cell homing and extravasation from the circulation to distant organs are also regulated by inflammatory chemokines. Recent experimental evidence demonstrated that besides leukocyte recruitment, tumor cell-derived CCL2 directly activated endothelial cells and together with monocytes facilitated tumor cell extravasation, in a CCL2- and CCL5-dependent manner. Furthermore, CX3CL1 expression in the bone facilitated metastasis of CX3CR1 expressing tumor cells to this site. Current findings in preclinical models strongly suggest that inflammatory chemokines have an important role during metastasis and targeting of the chemokine axis might have a therapeutic potential.