Stem cells and the development of mammary cancers in experimental rats and in humans

Abstract

Evidence based on immunocytochemical staining and ultrastructure suggests that morphological gradations between epithelial and myoepithelial cells, and possibly between epithelial cells and alveolar-like cells occur in terminal ductal structures of rat and human mammary glands. The benign carcinogen-induced rat and benign human mammary tumors can contain epithelial, myoepithelial-like and alveolar-like cells, whereas the malignant counterparts mainly contain only epithelial-like cells. Clonal epithelial cell lines from normal rat mammary glands, benign tumors, and SV40-transformed human mammary glands can differentiate to either myoepithelial-like or alveolar-like cells. In those of the rat, the differentiation processes occur in steps: intermediate cells along the myoepithelial-like pathway resemble intermediates in terminal ductal structures in vivo, and can also generate certain well-differentiated mesenchymal elements of the original tumours. Differentiation of the benign rat cells to alveolar-like cells with mammatrophic hormones and retinoids in vitro leads to a reduction in their tumor-forming ability in vivo. Cell lines from malignant rat mammary tumors of increasing metastatic potential and from human ductal carcinomas largely fail to yield myoepithelial-like or alveolar-like cells and are relatively slow-growing. Growth of the rat mammary epithelial cells in culture is stimulated by a pituitary-derived mammatrophic growth factor (PMGF), prostaglandin E2, and alpha-transforming growth factor; the response of the malignant cell lines to PMGF is reduced. It is suggested that stem cells exist in the rat and human glands that are capable of differentiating to the other major cell types of the mammary parenchyma, and that during the carcinogenic process they generate genetically unstable cells which lose their ability to differentiate and attempt to maximise their intrinsically slow growth rate.

Sequential alteration of peanut agglutinin binding-glycoprotein expression during progression of murine mammary neoplasia

“…This implies that initial conditions (differentiated phenotype) might be important. The expression of differentiation related carbohydrates recognisable by lectins was reported for several systems including hematopoietic cells (Reimann et al, 1984), endothelium (Alroy et al, 1987) and mammary epithelium (Rudland, 1987). The latter comprises several phenotypically distinct cell populations (Rudland, 1987;Sonnenberg et al, 1986).…”

“…Interestingly, in rat and humans the main populations can be classified on the basis of their PNA binding patterns (Rudland, 1987;Newman et al, 1979). In these studies ductal and alveolar cells bound the lectin with or without neuraminidase treatment, respectively.…”

“…Despite the wealth of information on tumour associated carbohydrate structures it is unclear whether multiple sequential genetic and phenotypic alterations driving tumour progression (Chen et al, 1989 and references therein) are paralleled by a particular sequence of changes in cell glycosylation patterns. On the other hand, the expression of certain carbohydrates seems to be associated with differentiation of cell components of the normal mammary gland (Rudland, 1987;Rudland et al, 1989). In particular, differential binding of Peanut agglutinin (PNA) to mammary cell subsets such as alveolar, ductal, myoepithelial, and stromal cells was reported in both human and rat systems (Rudland, 1987;Newman et al, 1979).…”

“…On the other hand, the expression of certain carbohydrates seems to be associated with differentiation of cell components of the normal mammary gland (Rudland, 1987;Rudland et al, 1989). In particular, differential binding of Peanut agglutinin (PNA) to mammary cell subsets such as alveolar, ductal, myoepithelial, and stromal cells was reported in both human and rat systems (Rudland, 1987;Newman et al, 1979). In our experience, also, murine epithelium but not stroma is rich in PNA binding sites.…”

Myoepithelial Cells: Their Origin and Function in Breast Morphogenesis and Neoplasia

“…It is also postulated and generally accepted that primary breast carcinomas show a dramatic increase in the ratio of luminal-to-myoepithelial cells, and that many invasive breast carcinomas essentially lack myoepithelial cells entirely (60). If the criteria for identification of myoepithelial cells were the expression of a complete differentiation program, then this strongly held belief is reasonable and correct.…”