Abstract
Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and ultimately to disseminate to distant sites. When a cancer cell metastasizes, it first will be exposed to cancer associated fibroblasts in the immediate tumor microenvironment and then to normal fibroblasts as it traverses the underlying connective tissue towards the bloodstream. The interaction of tumor cells with stromal fibroblasts influences tumor biology by mechanisms that are not yet fully understood. Here, we report a role for normal stroma fibroblasts in the progression of invasive tumors to metastatic tumors. Using a coculture system of human metastatic breast cancer cells (MCF10CA1a) and normal murine dermal fibroblasts, we found that medium conditioned by cocultures of the two cell types (CoCM) increased migration and scattering of MCF10CA1a cells in vitro, whereas medium conditioned by homotypic cultures had little effect. Transient treatment of MCF10CA1a cells with CoCM in vitro accelerated tumor growth at orthotopic sites in vivo, and resulted in an expanded pattern of metastatic engraftment. The effects of CoCM on MCF10CA1a cells were dependent on small amounts of active TGF-β1 secreted by fibroblasts under the influence of the tumor cells, and required intact ALK5-, p38-, and JNK signaling in the tumor cells. In conclusion, these results demonstrate that transient interactions between tumor cells and normal fibroblasts can modify the acellular component of the local microenvironment such that it induces long-lasting increases in tumorigenicity and alters the metastatic pattern of the cancer cells in vivo. TGF-β appears to be a key player in this process, providing further rationale for the development of anti-cancer therapeutics that target the TGF-β pathway.
Highlights
Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and to disseminate to distant sites
We investigated the crosstalk between human metastatic breast cancer cells (MCF10CA1a hereafter referred to as CA1a) and fibroblasts (DF) in a two-dimensional coculture system
Cocultures of CA1a and dermal fibroblasts (DF) formed an organized structure of tumor cell islets that were surrounded by elongated fibroblasts (Fig. 1A) [18]
Summary
Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and to disseminate to distant sites. As much as 50% or more of tumor bulk consists of non-parenchymal cells often referred to as the tumor microenvironment, including immune cells, cells of the microvasculature, and fibroblasts. Cells of the tumor parenchyma and stroma engage in extensive crosstalk, and the composition of the stroma and the nature of tumor stromal interactions change over time with tumor progression [1,2]. Tumor-stroma cross-talk influences tumor growth by regulating angiogenesis, suppressing or subverting host immune responses, modulating extracellular matrix, and secreting signaling molecules which in turn act on cells to further alter cell physiology and to change the composition of the cellular and acellular tumor microenvironment [2,3,4].
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