Serial transplants of DMBA-induced mammary tumors in Fischer rats as modelsystem for human breast cancer: V. Myoepithelial-mesenchymal conversion during passaging as possible cause for modulation of pineal-tumor interaction

An elevation of melatonin secretion parallel to an enhanced production of m acrophage-derived biopterin was observed in female F344 Fischer rats bearin g passage 2 serial transplants derived from a malignant mammary tumor induc ed by 7,1 2-dimethylbenz[a]anthracene (DMBA). As opposed to that both param eters were depressed at passage 12. These results indicate the presence of divergent immunoneuroendocrine interactions during different phases of tumo r growth. Since these biochemical events must have their common origin in c hanges taking place within these tumor transplants the current histopatholo gical study was initiated. The primary tumor used for serial transplantation was a moderately differen tiated adenocarcinoma of the mammary gland showing cytokeratin-positive epi thelial components located in the inner epithelial tubule layer In addition , bland-looking round or elongated actin-positive myoepithelial cells were detected which apart from epithelial cells are known to constitute the main cellular components of the mammary ductal system which resemble smooth mus cle cells both morphologically and functionally. The tumor of passage 1 sho wed glandular tubules, lined by an inner epithelial layer, and many nests o f clear, bland-looking actin-positive myoepithelial cells lying around tubu les as well as in the stroma between actin-negative epithelial elements. Th e tumor of passage 2 used for transplantation consisted of a chaotic mixtur e of epithelial carcinomatous cells, forming a few irregular small tubules or solid nests, and, predominantly, of elongated plump or spindle-shaped, " myoid" atypical myoepithelial cells with a strong actin-positive reaction a nd some of these cells showed a focal vimentin expression. The tumor was ch aracterized as a carcinosarcoma. At passage 12 epithelial cells were not id entified. The tumor displayed features of a pleomorphic sarcoma consisting mainly of giant cells with bizarre nuclei being cytokeratin- and desmin-neg ative, weakly vimentin-positive but strongly actin-positive. These results indicate that DMBA-induced mammary tumor cells in female F344 Fischer rats undergo dramatic morphological changes during serial transpla ntation characterized by a total loss of malignant epithelial (carcinomatou s) cells and the emergence and subsequent predominance of malignant (sarcom atous) mesenchymal cells. It appears that these sarcomatous cells develop o ut of myoepithelial cells since atypical myoepithelial cells with a strong actin-positive reaction showed a focal vimentin expression at passage 2 ind icating myofibroblastic differentiation as part of mesenchymal transition. The loss of epithelial cell elements as well as a parallel transition of my oepithelial to mesenchymal cell elements during passaging could lead to a l ack of immunological recognition of these tumor transplants and to depressi on of melatonin. Possible mechanisms involved in these phenomena as well as the relevance of these findings for a better understanding of the role of melatonin in human mammary cancer are discussed.