Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment

Abstract

Summary Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate--the cranial vault--, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate’s role as a driver of alveolar soft part sarcomagenesis.

Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner

“…Importantly, treatment with lactate by itself did not alter the basal expression or secretion of the pro-inflammatory factors ( data not shown ). Lactate tissue levels may vary from 1 mM to 10 mM depending on tissue and metabolic state [19], and in pathological situation such as cancer these levels may be increased 2-to-5-fold [20–23]. Furthermore, some bacterial infections [8] may also rise tissue lactate levels from 10 to 30 mM.…”

The ever-expanding role of HIF in tumour and stromal biology

“…Elevated lactate levels in tumours promotes M2 polarization in a HIF-1α dependent manner, indicating that hypoxic metabolism by tumour cells also impacts macrophage polarization 121 . These findings indicate that a combination of microenvironmental hypoxia and metabolic symbiosis between tumour cells and macrophages skew their polarization and shape the anti-tumour immune response 122,123 . In addition to mediating immunosuppression, M2 macrophages are important drivers of angiogenesis, indicating an intricate cross talk between hypoxic tumour cells, macrophages and endothelial cells that dictates oxygen availability in the tumour, cellular metabolism, and the anti-tumour immune response 124 .…”

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

“…14 MCTs have been identified, however, only MCTs 1–4 are able to transport monocarboxylates bidirectionally [27]. Both MCT1 and MCT4 have been identified as playing an important role in the metabolic relationship between cancer cells and fibroblasts [1] [28] [29] [30] [31]. Specifically, MCT1 has been found to be upregulated in OXPHOS cancer cells that have increased uptake of lactate while MCT4, on the other hand, is upregulated in lactate exporting, glycolytic cells [12] [30] [32].…”