Tumor necrosis factor-alpha-converting enzyme activities and tumor-associated macrophages in breast cancer

Abstract

The role of the tumor microenvironment especially of tumor-associated macrophages (TAMs) in the progression and metastatic spread of breast cancer is well established. TAMs have primarily a M2 (wound-healing) phenotype with minimal cytotoxic activities. The mechanisms by which tumor cells influence TAMs to display a pro-tumor phenotype are still debated although the key roles of immunomodulatory cytokines released by tumor cells, including colony-stimulating factor 1, tumor necrosis factor (TNF) and soluble TNF receptors 1/2, soluble vascular cell adhesion molecule 1, soluble interleukin 6 receptor and amphiregulin, have been demonstrated. Importantly, these factors are released through ectodomain shedding by the activities of the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17). The role of TACE activation leading to autocrine effects on tumor progression has been extensively studied. In contrast, limited information is available on the role of tumor cell TACE activities on TAMs in breast cancer. TACE inhibitors, currently in clinical trials, will certainly affect TAMs and subsequently treatment outcomes based on the substrates it releases. Furthermore, whether targeting a subset of the molecules shed by TACE, specifically those leading to TAMs with altered functions and phenotype, holds greater therapeutic promises than past clinical trials of TACE antagonists' remains to be determined. Here, the potential roles of TACE ectodomain shedding in the breast tumor microenvironment are reviewed with a focus on the release of tumor-derived immunomodulatory factors shed by TACE that directs TAM phenotypes and functions.

IL-6, IL-8 and TNF-α levels correlate with disease stage in breast cancer patients

“…The authors speculate that the main TNF-α producing cells (such as macrophages) may not be affected by ER, PR or HER2 expression, which could explain this result. 28,29 Another possibility is that the production of TNF-α is not only correlated with IL-8 levels, but also associated with other factors, such as IL-1β. 4,30 In this study, a correlation was found between cytokine levels and tumor stages, lymph node metastasis, and the ER, PR and HER2 status of tumors.…”

Chemotherapy-related cognitive impairment in older patients with cancer

“…17–37 Several neuroimaging studies in patients with cancer show the impact of cancer and chemotherapy on brain structure and function, revealing white and gray matter loss, altered resting state metabolism changes and altered white matter integrity, and brain activation upon cognitive task challenge. 38–55 Additionally, alleles in genes APOE and COMT have been linked to CRCI, suggesting that lipid metabolism, neural repair and neurotransmitter signaling also play a role in CRCI.…”

Prevalence, mechanisms, and management of cancer-related cognitive impairment

“…Cancer patients have increased levels of circulating cytokines (compared to healthy controls) (Korkaya et al, 2011; Rego et al, 2013), and inflammation has been associated with chemotherapy treatment and cognitive dysfunction(Janelsins et al, 2012), supporting a role for dysregulated immune function in the predisposition or perpetuation of CRCI. It is well established that inflammation plays a role in cognitive dysfunction and “sickness behavior” (e.g.…”