MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: A new rationale for the pathogenesis of osteolytic bone metastases

Abstract

Recent progress in dissecting the molecular paracrine circuits of cancer and stromal cells in bone metastases (BM) are offering new options to improve current merely palliative approach. The study of tumor-stroma metabolic interplay may further ameliorate this scenario. In this context, we demonstrated that highly glycolytic MDA-MB-231 cancer cells, that form osteolytic BM in vivo, release a large amount of lactate at a significantly higher level than MCF7 cells. Thus, we speculated that lactate released from carcinoma cells is uptaken and metabolically used by osteoclasts, the key players of osteolysis associated with BM. First, we demonstrated that the release of lactate at the bone site is mediated by monocarboxylate transporter 4 (MCT4), as revealed by immunostaining and MCT4 localization at the plasma membrane of tumor cells in mouse model of BM and in human tissue sections of BM. Then, we showed that in vitro lactate is uptaken by osteoclasts to be used as a fuel for the oxidative metabolism of osteoclasts, ultimately enhancing Type I collagen resorption. The passive transport of lactate into osteoclasts was mediated by MCT1: MCT1 expression is significantly upregulated during osteoclast differentiation and Type I collagen resorption is significantly impaired when osteoclasts are treated with 7-(N-benzyl-N-methylamino)-2-oxo-2H-chromene-3-carboxylic acid, an MCT-1 inhibitor. Together, these data demonstrate that lactate released by glycolytic breast carcinoma cells in the bone microenvironment promotes the formation of osteolytic lesions, and provide the rationale for further studies on the use of MCT1 targeting as a novel therapeutic approach in advanced cancer patients with BM.

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…Specifically, expression of the three enzymes required for de novo serine synthesis, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH), as well as the serine transporter SLC1A4, was observed to be significantly higher in bone-metastatic variants of breast tumors (Pollari et al, 2011). Similarly, bone metastatic breast cancer cells, when compared to the non-osteotropic ones, have also been observed to release large amounts of lactate (Lemma et al, 2017). Lactate is an important fuel for osteoclasts suggesting that osteotropic tumor cells release lactate to support osteolysis (Figure 4).…”

“…Lactate is an important fuel for osteoclasts suggesting that osteotropic tumor cells release lactate to support osteolysis (Figure 4). In fact, inhibition of the lactate transporter MCT-1 in the osteoclasts significantly impaired their osteolytic function (Lemma et al, 2017). Through the release of serine and lactate, cancer cells are able to form osteolytic bone metastases by promoting the differentiation and metabolic fitness of osteoclasts, allowing them to invade the metastatic niche and free up nutrients and space (Figure 4).…”

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

“…Lemma et al 35 showed that lactate released from breast cancer cells promoted osteoclast activation and the formation of osteolytic lesions as a source of energy. L-lactate is an essential metabolite of glycolysis, and the importance of lactate in osteoclast and bone metabolism has been reported.…”

“…L-lactate is an essential metabolite of glycolysis, and the importance of lactate in osteoclast and bone metabolism has been reported. Lemma et al 35 showed that lactate released from breast cancer cells promoted osteoclast activation and the formation of osteolytic lesions as a source of energy. In our present study, L-lactate concentration in the medium was reduced by the blockage of PFKFB3 during osteoclast differentiation and administration of L-lactate partially reversed the repression of osteoclastogenesis caused by PFKFB3 inhibition.…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…Indeed, MCTs are often upregulated in BC tissue [200], and MCT4 is a clear therapeutic target, at least in certain subtypes of BC [44]. Thus, targeting lactate transport with MCT inhibitors such as Quercetin suppresses BC growth and improves tumor immune response [76,184,201,278]. Other MCT inhibitors such as Simvastatin and Phloretin have also been found active against BC cells [77,228] (Table 2).…”