Progression of mouse mammary tumors: MCP‐1‐TNFα cross‐regulatory pathway and clonal expression of promalignancy and antimalignancy factors

• Published in: International journal of cancer 2003-10, Vol.106 (6), p.879-886
• Main Authors: Neumark, Eran, Sagi‐Assif, Orit, Shalmon, Bruria, Ben‐Baruch, Adit, Witz, Isaac P.
• Format: Article
• Language: English
• Subjects: Animal tumors. Experimental tumors; Biological and medical sciences; Experimental genital and mammary tumors; IL‐6; IP‐10; matrix metalloproteinases; MCP‐1; Medical sciences; TNFα; tumor heterogeneity; tumor microenvironment; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11337

The progression of breast cancer is affected by multiple cellular and microenvironmental components. The monocyte chemoattractant MCP‐1, IL‐6 and matrix metalloproteinases (MMP) were suggested to promote, each on its own, breast cancer progression. We recently demonstrated that the high‐tumorigenicity phenotype of the DA3 and CSML murine mammary adenocarcinoma cells is correlated with a high expression of MCP‐1, IL‐6 and MMP. This raised the possibility that common intrinsic tumor‐derived 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‐1, IL‐6 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‐high). We also determined the secretion of the antimalignancy chemokine IP‐10 from these cells. The results indicate that the secretion levels of IL‐6, MMP and IP‐10 varied between the clones. In contrast, all the clones secreted uniformly high levels of MCP‐1, suggesting that MCP‐1 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 vice versa. These findings indicate that the 3 promalignancy factors are not coregulated by a common intrinsic tumor‐derived factor. Rather, these results suggest that the individual capacities of the different clones to secrete these factors are summed up in the high‐malignancy DA3 parental tumor population, which secretes relatively high levels of MCP‐1, IL‐6 and MMP as compared to DA3 cells expressing a low‐malignancy phenotype. In contrast to the lack of coordinated intrinsic regulation of MCP‐1, IL‐6 and MMP, it was found that recombinant TNFα, a product of tumor‐associated macrophages contributing to breast cancer progression, upregulated the secretion of MCP‐1, IL‐6 and MMP from all the clones. These results suggest a key role for this microenvironmental, monocyte‐derived cytokine in the coordinated regulation of these 3 molecules. Furthermore, additional results demonstrated that monocytic cell‐derived TNFα upregulated MCP‐1 secretion from the tumor cells and that MCP‐1 in turn promoted the secretion of TNFα from monocytic cells. This may result in a positive feedback loop, whereby the tumor cells and the monocytic cells at tumor sit