{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T07:34:25Z","timestamp":1770968065407,"version":"3.50.1"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2003,6,26]],"date-time":"2003-06-26T00:00:00Z","timestamp":1056585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2003,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The progression of breast cancer is affected by multiple cellular and microenvironmental components. The monocyte chemoattractant MCP\u20101, IL\u20106 and matrix metalloproteinases (MMP) were suggested to promote, each on its own, breast cancer progression. We recently demonstrated that the high\u2010tumorigenicity phenotype of the DA3 and CSML murine mammary adenocarcinoma cells is correlated with a high expression of MCP\u20101, IL\u20106 and MMP. This raised the possibility that common intrinsic tumor\u2010derived factors regulate the concordant expression of these 3 components. The aim of the present study was to gain insight into the mode by which the secretion of MCP\u20101, IL\u20106 and MMP from murine mammary adenocarcinoma cells is regulated. This was investigated in cellular clones established from a highly malignant variant of the DA3 tumor (DA3\u2010high). We also determined the secretion of the antimalignancy chemokine IP\u201010 from these cells. The results indicate that the secretion levels of IL\u20106, MMP and IP\u201010 varied between the clones. In contrast, all the clones secreted uniformly high levels of MCP\u20101, suggesting that MCP\u20101 constitutes an important feature of the malignancy phenotype of mammary carcinoma. In most of the clones, elevated levels of 1 of the 3 promalignancy factors did not correlate with a high expression of the other 2 factors and <jats:italic>vice versa<\/jats:italic>. These findings indicate that the 3 promalignancy factors are not coregulated by a common intrinsic tumor\u2010derived factor. Rather, these results suggest that the individual capacities of the different clones to secrete these factors are summed up in the high\u2010malignancy DA3 parental tumor population, which secretes relatively high levels of MCP\u20101, IL\u20106 and MMP as compared to DA3 cells expressing a low\u2010malignancy phenotype. In contrast to the lack of coordinated intrinsic regulation of MCP\u20101, IL\u20106 and MMP, it was found that recombinant TNF\u03b1, a product of tumor\u2010associated macrophages contributing to breast cancer progression, upregulated the secretion of MCP\u20101, IL\u20106 and MMP from all the clones. These results suggest a key role for this microenvironmental, monocyte\u2010derived cytokine in the coordinated regulation of these 3 molecules. Furthermore, additional results demonstrated that monocytic cell\u2010derived TNF\u03b1 upregulated MCP\u20101 secretion from the tumor cells and that MCP\u20101 in turn promoted the secretion of TNF\u03b1 from monocytic cells. This may result in a positive feedback loop, whereby the tumor cells and the monocytic cells at tumor site promote each other's ability to express and secrete promalignancy factors. We next attempted to assess the contribution of the promalignancy factors MCP\u20101, IL\u20106 and MMP and of the antimalignancy factor IP\u201010 to mammary adenocarcinoma progression. To this end, a preliminary formula was developed in which the net balance between secretion levels of the promalignancy factors and that of the antimalignancy IP\u201010 chemokine from different clones was related to their <jats:italic>in vivo<\/jats:italic> tumorigenicity profile. This formula suggests that a balance between the secretion levels of these factors plays an important role in determining the malignancy phenotype of mammary carcinomas. In all, our findings demonstrate that the mammary tumor cell population is composed of a heterogeneous assortment of clones whose individual characteristics are averaged in the whole population. The malignancy potential of such tumors is thus determined, <jats:italic>inter alia<\/jats:italic>, by a combinatorial effect of several promalignancy and antimalignancy factors secreted from each of the clones comprising these tumors. Our results also suggest that the expression of such factors is determined by several nonmutually exclusive regulatory mechanisms. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11337","type":"journal-article","created":{"date-parts":[[2003,8,11]],"date-time":"2003-08-11T13:45:48Z","timestamp":1060609548000},"page":"879-886","source":"Crossref","is-referenced-by-count":58,"title":["Progression of mouse mammary tumors: MCP\u20101\u2010TNF\u03b1 cross\u2010regulatory pathway and clonal expression of promalignancy and antimalignancy 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