Extracellular Lactic Acidosis of the Tumor Microenvironment Drives Adipocyte-to-Myofibroblast Transition Fueling the Generation of Cancer-Associated Fibroblasts

Abstract

Lactic acidosis characterizes the tumor microenvironment (TME) and is involved in the mechanisms leading to cancer progression and dissemination through the reprogramming of tumor and local host cells (e.g., endothelial cells, fibroblasts, and immune cells). Adipose tissue also represents a crucial component of the TME which is receiving increasing attention due to its pro-tumoral activity, however, to date, it is not known whether it could be affected by the acidic TME. Now, emerging evidence from chronic inflammatory and fibrotic diseases underlines that adipocytes may give rise to pathogenic myofibroblast-like cells through the adipocyte-to-myofibroblast transition (AMT). Thus, our study aimed to investigate whether extracellular acidosis could affect the AMT process, sustaining the acquisition by adipocytes of a cancer-associated fibroblast (CAF)-like phenotype with a pro-tumoral activity. To this purpose, human subcutaneous adipose-derived stem cells committed to adipocytes (acADSCs) were cultured under basal (pH 7.4) or lactic acidic (pH 6.7, 10 mM lactate) conditions, and AMT was evaluated with quantitative PCR, immunoblotting, and immunofluorescence analyses. We observed that lactic acidosis significantly impaired the expression of adipocytic markers while inducing myofibroblastic, pro-fibrotic, and pro-inflammatory phenotypes in acADSCs, which are characteristic of AMT reprogramming. Interestingly, the conditioned medium of lactic acidosis-exposed acADSC cultures was able to induce myofibroblastic activation in normal fibroblasts and sustain the proliferation, migration, invasion, and therapy resistance of breast cancer cells in vitro. This study reveals a previously unrecognized relationship between lactic acidosis and the generation of a new CAF-like cell subpopulation from adipocytic precursor cells sustaining tumor malignancy.

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

“…Most recently, a new subpopulation of CAFs generated by lactic acidosis has been described, consisting of the acquisition of a CAF-like phenotype by adipocyte precursors. These adipocyte-derived CAFs display protumorigenic activity, sustaining proliferation, migration, invasion, and therapy resistance to BC cells [57].…”

“…The most recent experimental evidence consistently demonstrates that mammary adipocytes, during BC progression, de-differentiate into myofibroblasts and macrophage-like cells through metabolic reprogramming. Lactic acidosis promotes the adipocyte-myobroblast transition in a pre-fibrotic and pro-inflammatory environment [57,68]. These myofibroblasts have lost the adipocyte differentiation markers, produce pro-inflammatory cytokines, and are responsible for extracellular matrix synthesis/deposition and remodeling, eventually exerting a protumorigenic role [57].…”

“…Lactic acidosis promotes the adipocyte-myobroblast transition in a pre-fibrotic and pro-inflammatory environment [57,68]. These myofibroblasts have lost the adipocyte differentiation markers, produce pro-inflammatory cytokines, and are responsible for extracellular matrix synthesis/deposition and remodeling, eventually exerting a protumorigenic role [57].…”

The Role of Mesenchymal Stem Cells in Modulating the Breast Cancer Microenvironment

“…iCAFs promote breast cancer progression by attracting myeloid cells through the production of CCL2 and by enhancing invasive activity via MMPs 106 . Furthermore, CAFs can also originate from MSCs 107 and adipocytes 108 in breast cancer. The interaction between MSCs and CAFs is mainly studied in the context of their transformation.…”

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

“…Also common is the enhanced carcinoma cell ability to actively import fatty acids and their multimeric composites from their surroundings [ 26 , 54 , 55 , 56 , 57 , 58 ]. Finally, carcinoma cells interact with and reciprocally manipulate surrounding stromal cells to procure elevated access to the lipids these support cells can manufacture and export [ 32 , 57 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”