Principles of premetastatic niche formation

The article is devoted to premetastatic niche as a complex term, including stromal cells, vessels, extracellular matrix and their changes during interaction with the primary tumor. On example of different malignant tumors authors describe as primary tumor through tumor exosomes prepares certain organs-recipients to metastatic clone implantation. In the area of premetastatic niche under the influence of tumorous exosomes polarization of macrophages towards M2 type takes place. The cells are the main agents, providing survival as well as migration of tumorous cells. Affecting extracellular matrix, macrophages change the microcirculatory bed permeability. This mechanism is directed towards increase of its permeability to entrance of metastatic clone cells form vessels into premetastatic niche. Besides macrophages fibroblasts and polypotent bone marrow stem cells are also reprogrammed, that results in metabolism and local immunity changes at the place of future implantation. As a result, only when tissue of recipient-organ is prepared for contact with metastatic clone, their interaction take place with consequent formation of secondary tumor metastatic niche. Thus, this review describes pathogenesis of metastasis, different from its early understanding as spread of metastatic clone with lymph and blood. These peculiarities may in future have significant impact in practical medicine, Blockage of signal spread from primary tumor through exosomes is one of the promising directions in pathogenetic therapy of malignant tumors. Investigation of principles of premetastatic niche formation may become a theoretical substantiation for prophylaxis of metastatic disease and inhibition of micrometastasis to macrometastasis transformation.

A Novel Function of Syndecan-2, Suppression of Matrix Metalloproteinase-2 Activation, Which Causes Suppression of Metastasis

The syndecans comprise a family of cell surface heparan sulfate proteoglycans exhibiting complex biological functions involving the interaction of heparan sulfate side chains with a variety of soluble and insoluble heparin-binding extracellular ligands. Here we demonstrate an inverse correlation between the expression level of syndecan-2 and the metastatic potential of three clones derived from Lewis lung carcinoma 3LL. This correlation was proved to be a causal relationship, because transfection of syndecan-2 into the higher metastatic clone resulted in the suppression of both spontaneous and experimental metastases to the lung. Although the expression levels of matrix metalloproteinase-2 (MMP-2) and its cell surface activators, such as membrane-type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinase-2, were similar regardless of the metastatic potentials of the clones, elevated activation of MMP-2 was observed in the higher metastatic clone. Removal of heparan sulfate from the cell surface of low metastatic cells by treatment with heparitinase-I promoted MMP-2 activation, and transfection of syndecan-2 into highly metastatic cells suppressed MMP-2 activation. Furthermore, transfection of mutated syndecan-2 lacking glycosaminoglycan attachment sites into highly metastatic cells did not have any suppressive effect on MMP-2 activation, suggesting that this suppression was mediated by the heparan sulfate side chains of syndecan-2. Actually, MMP-2 was found to exhibit a strong binding ability to heparin, the dissociation constant value being 62 nm. These results indicate a novel function of syndecan-2, which acts as a suppressor for MMP-2 activation, causing suppression of metastasis in at least the metastatic system used in the present study.