Breast Cancer Tumor Stroma: Cellular Components, Phenotypic Heterogeneity, Intercellular Communication, Prognostic Implications and Therapeutic Opportunities

Abstract

Although the mechanisms underlying the genesis and progression of breast cancer are better understood than ever, it is still the most frequent malignant tumor in women and one of the leading causes of cancer death. Therefore, we need to establish new approaches that lead us to better understand the prognosis of this heterogeneous systemic disease and to propose new therapeutic strategies. Cancer is not only a malignant transformation of the epithelial cells merely based on their autonomous or acquired proliferative capacity. Today, data support the concept of cancer as an ecosystem based on a cellular sociology, with diverse components and complex interactions between them. Among the different cell types that make up the stroma, which have a relevant role in the dynamics of tumor/stromal cell interactions, the main ones are cancer associated fibroblasts, endothelial cells, immune cells and mesenchymal stromal cells. Several factors expressed by the stroma of breast carcinomas are associated with the development of metastasis, such as matrix metalloproteases, their tissular inhibitors or some of their regulators like integrins, cytokines or toll-like receptors. Based on the expression of these factors, two types of breast cancer stroma can be proposed with significantly different influence on the prognosis of patients. In addition, there is evidence about the existence of bi-directional signals between cancer cells and tumor stroma cells with prognostic implications, suggesting new therapeutic strategies in breast cancer.

MMP11 expression in intratumoral inflammatory cells in breast cancer

“…In summary, MMP11 expression by stromal cells (CAFs and MICs) contributes to breast cancer aggressivity (expression of pro‐tumoral factors by cancer cells, greater invasion and angiogenesis capacity and a higher rate of metastasis development). This is in agreement with other studies supporting the role of stroma in breast cancer (for review, see Eiro et al …”

Colorectal Cancer Stem Cells in the Progression to Liver Metastasis

“…Second, the bound form of CEACAM enhances the KC microenvironment by activating fibroblasts, which in turn facilitate CRC growth (139,141). ECM expression of the α5β1 integrin/fibronectin interaction then leads to cell survival (142)(143)(144). Finally, CEACAM5 upregulates adhesion molecules such as E-cadherin and N-cadherin, thereby promoting aggregation (cell survival) and metastasis (139,140,(144)(145)(146).…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…An abetting microenvironment is among the most prominent of the emerging hallmarks of cancer [19][20][21]. The secretory milieu of inflammatory mediators by cancer associated fibroblasts, immune cells, endothelial cells, and mesenchymal stromal cells is subverted by the ever adaptive tumor to overcome impediments to its growth, spread, and survival against treatment [22]. As drivers of resistance, cancer stem cells are protected by the tumor microenvironment through adaptation to nutritional, metabolic, and oxygen deprivation stresses [15].…”