Stromal Reaction to Invasive Cancer: The Cellular Origin of the Myofibroblast and Implications for Tumor Development

Abstract

Many epithelial malignancies are associated with an extensive conversion of the surrounding normal stroma reminiscent of the transient activation seen during wound healing, albeit in a more chronic form. The most outstanding feature of the altered stroma is the accumulation of peritumoral myofibroblasts. Here, I have focused on the cellular origin of myofibroblasts in human breast cancer, the tumor cell-derived activity responsible for their occurrence, and the possible function of their most pronounced cytoskeletal change. In the field of myofibroblast research, the use of newly developed cell-culture based technologies have been instrumental. Stromal cells in short-term cultures have been thoroughly characterized using markers defined by their staining patterns in the tissue of origin. Efforts t o purify nonactivated fibroblasts prior to cultivation and the introduction of chemically defined culture conditions have allowed the elements of conversion to be studied at the molecular level. Furthermore, the development of a so called tumor environment assay, in which tumor cell-stromal cell interactions result in functional replicas of typical tumor histology, has proven a powerful tool in the search for the contribution of the individual stromal cell types to the complex scenario of peritumoral myofibroblasts. The cell-cell interactions seen in the tumor environment assay have been validated by in vivo coinoculation of tumor cells and myofibroblasts in nude mice. The most recent data point t o the function of fibroblast cytoskeletal conversion in immobilizing the cells in close apposition to tumor cells. The comprehensive participation of norAddress correspondence and reprint requests to: Lone R~jnnov-Jessen, ma1 fibroblasts in malignancies promise for future new therapeutic strategies directed against tumor cell-fibroblast interaction.Key Words: fibroblast activation, a-sm actin, breast neoplasia ransition of preinvasive carcinoma to the invasive T phenotype coincides with radical changes in tissue organization with respect to cellular composition and extracellular matrix deposition. The most frequently encountered breast carcinoma, the infiltrating ductal carcinoma, is characterized by a particularly striking stromal response (desmoplasia) (1-4). The stromal reaction has at different times been reported either to promote or to inhibit tumor formation (2, 5) (for review see reference 6). However, although much attention has been focused on the variable contribution of stromal cells to tumor development (7-14), the complexity of the stroma still leaves much behind to discover. One of the hypotheses that has escaped the chaotic stromal scenario suggests that the observed differences might reflect a balance between the interactive processes at the invasive front versus the central part of the tumor (6). Clearly, the invasive front is different from the central sclerotic area in terms of cells and extracellular matrix. The invasive front is characterized by numerous stromal cells (myofibroblasts), tenascin, hyaluroni...

Breast cancer by proxy: can the microenvironment be both the cause and consequence?

“…We have shown previously that resident, normal fibroblasts readily undergo conversion to myofibroblasts in response to tumor cells in culture (reviewed in [3,18]). Multiple studies have documented that the converted stroma in turn supports cancer cell growth and metastasis [3,18–22].…”

Subcellular localization of early biochemical transformations in cancer-activated fibroblasts using infrared spectroscopic imaging

“…3,5 Similarly, when normal fibroblasts are stimulated with TGF-β1, a growth factor which is known to have multiple roles in tumor growth and the conditioning of the microenvironment, 6 α-SMA is expressed. α-SMA expression is measured using immunofluorescence, an antibody-based technique.…”

Role of tissue stroma in cancer cell invasion

“…It would be interesting to know whether the senescent fibroblasts are myofibroblasts expressing α-SMA. α-SMA-negative fibroblasts have a tendency to convert in culture with increasing lifespan towards terminally differentiated α-SMA-positive myofibroblasts [56,137].…”