Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

Abstract

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficient mice show reduced metastasis, with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin-neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.APBA3/Mint3 | macrophage | metastasis C ancer metastasis comprises multiple processes of neoplastic progression, termed the "invasion-metastasis cascade" (1, 2). Thousands of circulating tumor cells (CTCs) can be released from invasive primary tumors; however, most patients develop only a few metastases, suggesting that metastatic initiation processes (such as extravasation and colonization at distant organs) are quite inefficient but key for controlling metastatic cancer diseases. Unlike at primary sites, single or small groups of disseminated CTCs encounter large numbers of normal cells in their new environments, which determines their survival and metastatic efficiency, as shown by studies with genetically engineered mouse models (3-5).Macrophages are myeloid cells that are co-opted essentially to foster tumor progression and metastasis. The functions of tumorassociated macrophages include angiogenesis, suppression of antitumor immune responses, chemoresistance, and metastasis; these are considered novel targets for cancer therapy (6-10). Monocytes (i.e., macrophage precursors) are characterized by the surface molecules CD11b and CD115, and comprise at least two subsets: Gr-1 + (Ly-6C high )CCR2 + CX3CR1 low inflammatory monocytes (IMs) and Gr-1 low (Ly-6C low )CCR2 low CX3CR1 high resident monocytes (RMs) (11). Their recruitment from the bone marrow (BM) to peripheral tissues is mediated mainly by chemokine-chemokine receptor complexes such as the CCL2/CCR2 system (12, 13). Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM ...

Immune effector monocyte–neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer

“…On the one hand, there are data, in line with our work, showing that CCR2 + monocytes are cytotoxic (20) and antitumoral (37) and that CCL2 in breast cancer has an antimetastatic role (36,38,39). On the other hand, there are data showing that CCR2 + monocytes and CCL2 are involved in promoting metastatic breast cancer (40)(41)(42)(43)(44)(45). Notably, the great majority of prior studies showing that CCR2 + monocytes and CCL2 promote metastatic progression, have injected breast cancer cells i.v.…”

Smoking is a risk factor for pulmonary metastasis in colorectal cancer

“…It is necessary for metastasis to distant organs that the circulating tumour cells extravasate from the primary lesion, flow into the distant organ and then colonize it. Inflammatory monocytes of the organ enhance vascular permeability through vascular endothelial growth factor and induce the expression of E‐selectin (a cell adhesion molecule), leading to extravasation and colonization . We speculate that cigarette smoking could increase vascular permeability via inflammatory cytokines or physiological destruction due to fibrotic changes, which might promote influx of CRC cells into the lung.…”

Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1

“…Munc18-1-interacting protein 3 (Mint3) can activate HIF-1 even under normoxic conditions by binding to and suppressing FIH-1 without affecting protein levels of HIF-1α [11]. Mint3 itself is expressed ubiquitously, but Mint3mediated HIF-1 activation is limited to some types of cells, such as cancer cells, macrophages, and cancer-associated fibroblasts, mainly due to the necessity of matrix metalloproteinase 14 expression, which supports stable interactions between Mint3 and FIH-1 in cells [7,[12][13][14][15][16]. Previously, we revealed that Mint3 depletion reduces HIF-1 activity during normoxia and tumorigenicity in breast cancer and fibrosarcoma [15,17].…”