bims-stacyt 2020-11-15 papers

Biology (Basel). 2020 Nov 07. pii: E380. [Epub ahead of print]9(11):

Metabolic Cancer-Macrophage Crosstalk in the Tumor Microenvironment.

Kyra E de Goede, Amber J M Driessen, Jan Van den Bossche.

Tumors consist of a wide variety of cells, including immune cells, that affect tumor progression. Macrophages are abundant innate immune cells in the tumor microenvironment (TME) and are crucial in regulating tumorigenicity. Specific metabolic conditions in the TME can alter the phenotype of tumor-associated macrophages (TAMs) in a direction that supports their pro-tumor functions. One of these conditions is the accumulation of metabolites, also known as oncometabolites. Interactions of oncometabolites with TAMs can promote a pro-tumorigenic phenotype, thereby sustaining cancer cell growth and decreasing the chance of eradication. This review focuses on the metabolic cancer-macrophage crosstalk in the TME. We discuss how cancer cell metabolism and oncometabolites affect macrophage phenotype and function, and conversely how macrophage metabolism can impact tumor progression. Lastly, we propose tumor-secreted exosome-mediated metabolic signaling as a potential factor in tumorigenesis. Insight in these processes may contribute to the development of novel cancer therapies.

Keywords: TAM; cancer; macrophages; metabolism; oncometabolite; tumor; tumor-associated macrophage

DOI: https://doi.org/10.3390/biology9110380

Cancer Res. 2020 Nov 10. pii: canres.0256.2020. [Epub ahead of print]

A Notch-dependent inflammatory feedback circuit between macrophages and cancer cells regulates pancreatic cancer metastasis.

Yawen Geng, Jie Fan, Lianyu Chen, Chenyue Zhang, Chao Qu, Ling Qian, Kun Chen, Zhiqiang Meng, Zhen Chen, Peng Wang.

Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1 (JAG1). Auto-amplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream interleukin (IL)-8, CCL2, IL-1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL-6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell EMT and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-0256

Int J Mol Sci. 2020 Nov 07. pii: E8363. [Epub ahead of print]21(21):

Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity.

Joy X Wang, Stephen Y C Choi, Xiaojia Niu, Ning Kang, Hui Xue, James Killam, Yuzhuo Wang.

Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid's role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies.

Keywords: acidic tumor microenvironment; anticancer immunotherapy; cancer-induced immunosuppression; de-differentiation; epigenetic reprograming; lactic acid

DOI: https://doi.org/10.3390/ijms21218363