Upregulation of HMGB1 in tumor-associated macrophages induced by tumor cell-derived lactate further promotes colorectal cancer progression

Abstract

Background Lactate accumulation leads to an acidic tumor microenvironment (TME), in turn promoting colorectal cancer (CRC) progression. Tumor-associated macrophages (TAMs) are the predominant cells in TME. This study aimed to reveal the regulation mechanism of CRC cell-derived lactate on TAMs and explore the mechanism underlying lactate accumulation-induced aggravation in CRC. Methods Cell growth and metastasis were evaluated by colony formation, Transwell, and wound healing assays. Western blot and RT-qPCR were applied to determine the protein and mRNA expression. Flow cytometry was used to analyze the polarization state and apoptotic rate of macrophages induced in THP-1 cells. The lactate in the cell supernatant was quantified using an ELISA kit. Immunofluorescence was performed to visualize the location of High Mobility Group Box 1 (HMGB1). H&E and Ki67 staining assays were used to assess tumorigenesis in nude mice bearing ectopic tumors. Results Cell growth and metastasis were promoted in the hypoxic CRC cells. The hypoxic cell supernatant stimulated the M2-type polarization of macrophages. The lactate level increased in hypoxic cancer cells. However, the inhibition of lactate using 3-hydroxy-butyrate (3-OBA) reversed the effects of hypoxia. Also, macrophages showed no promoting effect on cancer cell growth and migration in the presence of 3-OBA. HMGB1 was secreted into the extracellular space of lactate-induced macrophages, further enhancing the malignant behaviors of cancer cells. ERK, EMT, and Wnt signaling pathways were activated in cancer cells due to HMGB1 upregulation. Conclusions The lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells.

GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression

“…To gain deeper insights into the mechanism of lactate-induced signaling through GPR65 on TAMs and its role in enhancing the malignant progression of glioma, we analyzed six potential cytokines and chemokines (CCL2, CCL5, CCL17, CCL18, HMGB1, and TGFB1) derived from TAMs, which were previously reported to be associated with lactate levels or pro-tumorigenic activities [ 14 , 15 , 18 , 33 , 40 ]. We found that the levels of HMGB1 was obviously elevated under lactate stimulation, which were also dropped down when GPR65 on TAMs was silenced (Fig.…”

“…In our study, we found that GPR65 + TAMs could affect the secretion of HMGB1, thereby facilitating the progression and mesenchymal transition of glioma cells. Corresponding to this, HMGB1 also could promote tumor progression in colorectal cancer by activating EMT, Wnt, and ERK signal pathway [ 14 ]. In our study, we found that GPR65 sensing lactate-stimulating promotes the expression and secretion of HMGB1 through cAMP/PKA/CREB pathway.…”

“…Typically, macrophages infiltrated in tumors, named tumor-associated macrophages (TAM), shows M2-polarization characteristics and promote tumor malignant progression by secreting a variety of cytokines ( e.g. , TGFB1 [ 13 ] and HMGB1 [ 14 ]) and chemokines ( e.g. , CCL17 [ 15 ] and CXCL7 [ 16 ]).…”

Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway

“…The lactate created by tumor glycolysis forms an acidic tumor microenvironment, under which TAMs are mostly differentiated into M2 type, often exhibiting effects such as promoting tumor cell growth, angiogenesis and cell metastasis 16 . Some studies have revealed that upregulation of HMGB1 in tumor cell‐derived lactic acid‐induced TAMs further stimulated colorectal cancer progression 28 . LncRNA HITT has also been found to diminish lactate creation by reducing PKM2 oligomerization to decline tumor growth and macrophage polarization 29 .…”

Implication of Obesity and Gut Microbiome Dysbiosis in the Etiology of Colorectal Cancer

“…It has been found to boost angiogenesis and provide oxygen and glucose to cancer cells, which in turn facilitates the growth, invasion, and migration of colon cells [ 169 ]. The lactate metabolized by cancerous cells exacerbates CRC progression by prompting macrophages to exhibit M2-type polarization and the production of high-mobility group box 1 (HMGB1), which is essential in maintaining nucleosome structure and controlling the transcription of many genes [ 170 ]. In addition, the accumulation of lactate in the TME creates an acidic environment that impairs the cytotoxic and effector capabilities of T cells, thus enabling tumors to escape the immune system and reducing the effectiveness of certain chemotherapy drugs, all of which have a detrimental influence on CRC prognosis [ 152 ].…”