Microenvironmental regulation of cancer development

Abstract

Numerous studies have demonstrated that the tumor microenvironment not only responds to and supports carcinogenesis, but also actively contributes to tumor initiation, progression, and metastasis. During tumor progression all cells composing the tumor undergo phenotypic and epigenetic changes. Paracrine signaling between epithelial and stromal cells is important for the regulation of the proliferation, invasive, angiogenic, and metastatic behavior of cancer cells. Better understanding the molecular mechanisms by which stromal cells exert these effects may open up new venues for cancer therapeutic and preventative interventions.

Figure 1. The dual role of bone marrow derived mesenchymal stem cells (BMD-MSCs) in cancer metastasis

1. Primary tumor cells send signals to the bone marrow mobilizing BMD-MSCs. 2. BMD-MSCs are recruited to the primary tumor (2a), and also mobilized to other organs such as lungs (2b), creating a pre-metastatic niche prior to the dissemination of the cancer cells. 3. The interaction between cancer cells and BMD-MSCs within the primary tumor enhances the motility, invasive and metastatic capacity of tumor cells via paracrine interactions (e.g., CCL5-CCR5). In addition, BMD-MSCs can differentiate into myofibroblasts and other stromal cell types that further support the growth and progression of the tumor. Furthermore, disseminated cancer cells preferentially grow at sites where BMD-MSCs are localized forming distant metastases.

Figure 2. Events involved in the in situ to invasive breast carcinoma transition

Progression to invasion is marked by the disappearance of myoepithelial layer, disruption of the basement membrane, accompanied by infiltration of leukocytes, accumulation of myofibroblasts, and intrusion of capillary vessels. High levels of MMPs produced by DCIS associated myoepithelial cells, fibroblasts, myofibroblasts, and leukocytes all contribute to the degradation of the basement membrane and tumor progression.