Diverse Roles of the Plasminogen Receptor, Plg‐RKT, in Mammary Tumor Development and Metastasis

Abstract

ObjectivesPlg‐RKT is a unique transmembrane plasminogen receptor, highly expressed on tumor cells and macrophages. We investigated the role of Plg‐RKT in mammary tumor incidence, development, growth and metastasis in a PyMT transgenic mouse mammary tumor model.MethodsPlg‐RKT deficiency was bred into PyMT mice to compare mammary tumor development in PyMT/Plg‐RKT+/+ and PyMT/Plg‐RKT−/− female littermates.ResultsMultifocal mammary tumor development was observed in all animals with no difference between genotypes in time of first appearance of palpable tumors. Mice in both groups developed mammary tumors in 3 – 10 mammary glands per animal. However, the mean number of tumors in PyMT/Plg‐RKT−/− mice was significantly less than in PyMT/Plg‐RKT+/+ mice. Tumors in PyMT/Plg‐RKT−/− mice grew more slowly than tumors in PyMT/Plg‐RKT+/+ mice. At 20 weeks of age, cumulative mammary tumor volumes and tumor weights were significantly less for PyMT/Plg‐RKT−/− mice. Histological examination revealed abundant fibrin deposition in mammary tumors in PyMT/Plg‐RKT−/− mice but not in PyMT/Plg‐RKT+/+ mice, suggesting dysregulated fibrin surveillance and markedly dysregulated plasminogen activation due to the absence of Plg‐RKT. Early mammary tumors also differed markedly in their morphology: mammary foci in PyMT/Plg‐RKT−/− mice were primarily adenomas and were surrounded by a pronounced collagen‐rich extracellular matrix; whereas PyMT/Plg‐RKT+/+ mice had large, hyperproliferative tumor nodules that were not completely surrounded by extracellular matrix.We compared lung metastasis in PyMT/Plg‐RKT−/− and PyMT/Plg‐RKT+/+ mice, expecting fewer metastases in PyMT/Plg‐RKT−/− mice due to their decreased mammary tumor burden. Surprisingly, at 20 weeks of age PyMT/Plg‐RKT−/− mice had more metastatic lung tumors and a higher metastatic burden when tumor cells in the lungs were quantified by PCR for PyMT transcript expression. To evaluate the influence of mammary tumor burden on metastasis, we analyzed metastasis in a small cohort (n=8) of PyMT/Plg‐RKT−/− mice that at 22 weeks of age, had developed a mammary tumor burden similar to PyMT/Plg‐RKT+/+ mice at 20 weeks. When comparing metastasis in these mice with comparable tumor size, the larger metastatic burden in PyMT/Plg‐RKT−/− mice was even more striking. Staining of lung tissues for the pan‐macrophage marker (F4/80) revealed marked infiltration of macrophages both in the lung parenchyma and peritumoral to lung foci in PyMT/Plg‐RKT+/+ but not PyMT/Plg‐RKT−/− mice.ConclusionsTogether these results show that Plg‐RKT supports mammary tumor development and growth, and suggest that Plg‐RKT alters the ECM to promote tumorigenesis. Conversely, Plg‐RKT inhibits tumor metastasis, possibly because Plg‐RKT on non‐tumor cells, i.e., monocytes/macrophages, contributes to an anti‐metastatic environment in the target organ.Support or Funding InformationHL 081046, CA166473, Merit Rev. #5I01BX002026This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.