The Presence of Cyclooxygenase 2, Tumor-Associated Macrophages, and Collagen Alignment as Prognostic Markers for Invasive Breast Carcinoma Patients

Abstract

Inflammation, and the organization of collagen in the breast tumor microenvironment, is an important mediator of breast tumor progression. However, a direct link between markers of inflammation, collagen organization, and patient outcome has yet to be established. A tumor microarray of 371 invasive breast carcinoma biopsy specimens was analyzed for expression of inflammatory markers, including cyclooxygenase 2 (COX-2), macrophages, and several collagen features in the tumor nest (TN) or the tumor-associated stroma (TS). The tumor microarray cohort included females, aged 18 to 80 years, with a median follow-up of 8.4 years. High expression of COX-2 (TN), CD68 (TS), and CD163 (TN and TS) predicted worse patient overall survival (OS). This notion was strengthened by the finding from the multivariate analysis that high numbers of CD163 macrophages in the TS is an independent prognostic factor. Overall collagen deposition was associated with high stromal expression of COX-2 and CD163; however, total collagen deposition was not a predictor for OS. Conversely, local collagen density, alignment and perpendicular alignment to the tumor boundary (tumor-associated collagen signature-3) were predictors of OS. These results suggest that in invasive carcinoma, the localization of inflammatory cells and aligned collagen orientation predict poor patient survival. Additional clinical studies may help validate whether therapy with selective COX-2 inhibitors alters expression of CD68 and CD163 inflammatory markers.

Factors associated with obesity alter matrix remodeling in breast cancer tissues

“…4) that we observe within tumor tissues compared to normal breast tissues is consistent with a number of studies performed with animal models and human tissue specimens. 3,43,44 Enhanced collagen fiber alignment, especially perpendicular to the tumor border, has been reported in several studies and is associated with enhanced metastatic potential, as the fibers are thought to serve as a conduit for tumor cells that are shed from the primary tumor and ultimately form metastases. 43,44 Such changes in alignment, along with enhanced collagen fiber cross-links, are also associated with increased tissue stiffness, which has been shown to activate important mechanosignaling cellular pathways that promote malignancy, invasion, and metastasis.…”

“…3,43,44 Enhanced collagen fiber alignment, especially perpendicular to the tumor border, has been reported in several studies and is associated with enhanced metastatic potential, as the fibers are thought to serve as a conduit for tumor cells that are shed from the primary tumor and ultimately form metastases. 43,44 Such changes in alignment, along with enhanced collagen fiber cross-links, are also associated with increased tissue stiffness, which has been shown to activate important mechanosignaling cellular pathways that promote malignancy, invasion, and metastasis. 6,[45][46][47][48] Statistically significant increases in fiber alignment and CAF are further enhanced within tumors excised from obese mice fed an HFD compared to tumors developed in mice fed a normal diet (Fig.…”

Facing the future: challenges and opportunities in adoptive T cell therapy in cancer

“…Endothelin B inhibition [122] Eicosanoids (PGE2) [132][133][134] COX-2 inhibitors [ [152]. CCR4 blockade [153].…”

“…PGE 2 is formed via the activity of cyclooxygenase-2 (COX-2) [131]. The presence of COX-2 and the M2 phenotype TAM marker CD163 is associated with poor prognosis in breast cancer, while perioperative therapy with COX-2 and beta-adrenergic blockers results in lower metastatic spread [132,133]. Similarly, PGE 2 and CD163 correlate to poor prognosis in pancreatic cancer [134].…”

The role of the adipose tissue microenvironment in kidney cancer

“…For example, an M2 phenotype skew for macrophages was observed in mice within the tumour-associated adipose tissue experiencing changes of lipid metabolism, which were favourable for cancer cell development [150]. Relevant research in humans is limited to the field of breast cancer with findings supporting that high M2 macrophage expression in adipose stroma of breast tumours predicted poor cancer prognosis [210,211]. As discussed previously, perinephric adipose tissue which is easily obtained after radical nephrectomy is an important but often ignored tumour-associated adipose tissue for kidney cancer [257].…”