MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

Abstract

Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteases MMP1 and MMP9 and inflammatory COX2 genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets.

Gene expression differences in adipose tissue associated with breast tumorigenesis

“…Increased levels of MMP9 have been found on M2 macrophages and are induced in promonocytes when co-cultured with breast cancer cells. 23 Together, these genetic changes not only suggest that tumor-adjacent adipose tissue has a heightened anti-inflammatory response when compared with distant fat but also that genes expressed in tumor-adjacent adipose tissue may promote cellular division, angiogenesis, and invasion, thus providing favorable conditions for breast tumor progression.…”

Profiling of circulating tumor cells in liquid biopsies from metastatic cancer patients

“…MMP1, MMP2, and MMP9 are metastatic genes involved in the invasion of tumor cells into underlying epithelium. [39] This is the first report that liquid biopsies from all cancer patients tested express high levels of MMP1, MMP2, and MMP9, providing a potential new avenue for treatment of metastatic cancers by suppression of these genes; however, these results require confirmation and further investigation. PBMC from five normal individual were tested and found to be negative for expression of cancer-related genes.…”

Analyzing the differentially expressed genes and pathway cross‐talk in aggressive breast cancer

“…showed that sulforaphane could downregulate mRNA of MMP families, such as MMP‐7 and ‐14, and reduce the production of pro‐inflammatory cytokines, immunomodulating cytokine and growth factors . Interestingly, previous study showed a relationship between aggressiveness of breast cancer epithelial cells and their ability to instruct immune cells to modify the expression of genes, such as proteases MMP‐1 and ‐9 . Therefore, these studies indirectly explained that screened DEG, such as MMP‐1, may be related to aggression in breast cancer.…”

“…MMP play an important role in the cancer invasion metastasis, angiogenesis and tumorigenicity, and it was considered as a candidate marker for identification of breast cancer . At the same time, MMP‐1 and cyclooxygenase‐2 were supported in co‐culture conditions by the promoted expression of proteases in the process of collagen degradation …”