Reversion toward an earlier stage of differentiation and loss of polarity during progression of N-methyl-N-nitrosourea-induced rat mammary tumours.

Abstract

To work toward an understanding of the mechanisms of cancer progression, we have followed the changes in expression of several genes in rat mammary carcinomas during the development of invasion. Tumors were induced by N-methyl-N-nitrosourea and serially transplanted to isogeneic rats. Gene expression in individual cells was followed by immunofluorescence microscopy. We show that invading cells do not express the same genes as the primary tumor or normal adult mammary gland but are similar to the primitive mammary duct cells present in late embryos. In the most advanced tumors, the most fundamental epithelial characteristic, polarity, is lost. Relative to the mechanism of invasion, we observe that the basal lamina, often thinner than normal, always coats the strands of invading cells and may be entirely absent from single invasive cells only. These observations suggest that the basal lamina ultimately disappears because of reduced expression of the genes or the failure to assemble the components. In these tumors it is the progressive alteration in gene expression rather than the enzymatic breakdown of the basal lamina that leads to invasion. These results show that the most important aspect of cancer progression is the progressive alteration of gene expression. They also raise questions about the mechanism that causes tumor cells to retrace the steps in their differentiation.

Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells.

“…The coordinated loss of BM around tumor cells and the lack of membrane polarity have been reported for N-methyl-N-nitrosourea-induced rat mammary tumors (45). In this study all normal luminal cultures showed basal expression of BM components and the normal primary cultures showed (46)(47)(48)(49).…”

Three-dimensional culture models of mammary gland

“…24,25 Early investigations suggested that this feature was due to altered gene expression for basement membrane proteins rather than any heightened enzymatic matrix breakdown. 26 This is further supported by evidence that breast carcinoma cells exhibit a downregulation in the laminin-binding integrin subunits. 27,28 As well as biochemical signaling from the extracellular matrix, cell-cell signaling mechanisms coordinate to maintain epithelial polarity and differentiation.…”

Biosynthesis and secretion of laminin and S‐laminin by human prostate carcinoma cell lines

“…Disruption of the basal lamina is a crucial event that occurs in early neoplastic invasion and is characterized by the loss or abnormal formation of the structure [7,8]. The altered basal lamina may be due to dissolution by secretion of proteases by the invasive cells [7] or a defective construction by either the altered production or deposition of its main components [9]. In addition, the continued production of some of the basal lamina components has been observed to confer an advantage to further stages of tumor progression.…”