Cancer Cell Metabolism: Implications for X-ray and Particle Radiation Therapy.

Mathieu Sertorio,Ralph E Vatner,Susanne I Wells,Yi Zheng,Anthony E Mascia,John P Perentesis

doi:10.14338/ijpt-18-00023.1

Abstract

Advances in radiation delivery technologies and immunotherapy have improved effective cancer treatments and long-term outcomes. Experimental and clinical trials have demonstrated the benefit of a combination of radiation therapy and immunotherapy for tumor eradication. Despite precise radiation dose delivery that is achievable by particle therapy and benefits from reactivating the antitumor immune response, resistance to both therapeutic strategies is frequently observed in patients. Understanding the biological origins of such resistance will create new opportunities for improved cancer treatment. Cancer metabolism and especially a high rate of aerobic glycolysis leading to overproduction and release of lactate is one such biological process favoring tumor progression and treatment resistance. Because of their known protumor effects, aerobic glycolysis and lactate production are potential targets for increased efficacy of radiation alone or in combination with immunotherapy. In the following review, we present an overview of the interplay of cancer cell lactate metabolism with the tumor microenvironment and immune cells. We discuss how a deeper understanding and careful modulation of lactate metabolism and radiation therapy might exploit this interplay for improved therapeutic outcome.

Highlights

Radiation therapy is a key treatment modality for noninvasive and targeted tumor therapy
Metabolic reprogramming in cancer cells was originally attributed to impaired mitochondrial activity but can occur by other means such as increased glycolytic enzyme expression following oncogene activation
Cancer cells can be induced to return to oxidative phosphorylation, and targeting mitochondria with this goal is being actively explored as a new approach to cancer therapy [60]

Summary

Introduction

Radiation therapy is a key treatment modality for noninvasive and targeted tumor therapy. The acidic extracellular environment directly promotes the transformation of nascent tumor cells and metabolic reprogramming therein, while selecting for clones that are resistant to transitory hypoxic conditions during tumor development [17] These effects on cancer cells are paracrine in that they require the export and uptake of lactate by the MCT receptors 1 and 4 and lactate signaling through its receptor GPR81 (Figure 1). Lactate-mediated acidosis has been shown to directly stimulate cancer cell motility, in part by increasing the expression and activation of proteolytic enzymes by adjacent cells leading to extracellular matrix remodeling [19] (Figure 1) In line with this role, bicarbonate treatment of mice for a reduction of pH in the tumor microenvironment decreased tumor invasion or metastases [20, 21]. These pathways could potentially be targeted with anti-VEGF antibodies or small molecules, mTOR pathway inhibitors, or proteasome-targeted drugs

Cancer Metabolism and Lactate Production Diminish Antitumor Immune Responses

Findings

Conclusion