Therapeutic implications of tumor interstitial acidification

Abstract

Interstitial acidification is a hallmark of solid tumor tissues resulting from the combination of different factors, including cellular buffering systems, defective tissue perfusion and high rates of cellular metabolism. Besides contributing to tumor pathogenesis and promoting tumor progression, tumor acidosis constitutes an important intrinsic and extrinsic mechanism modulating therapy sensitivity and drug resistance. In fact, pharmacological properties of anticancer drugs can be affected not only by tissue structure and organization but also by the distribution of the interstitial tumor pH. The acidic tumor environment is believed to create a chemical barrier that limits the effects and activity of many anticancer drugs. In this review article we will discuss the general protumorigenic effects of acidosis, the role of tumor acidosis in the modulation of therapeutic efficacy and potential strategies to overcome pH-dependent therapy-resistance.

Introduction

Tumor tissues are characterized by an intricate organization that cannot be viewed simply as the outgrowth of cancer cells clones within a normal tissue. Instead, they consist of multiple cell types (both transformed and non-transformed) that cooperate through diverse mechanisms to maintain the microenvironment favorable for tumor cells survival and progression [1]. Unlike normal tissues with a structured capillary system that provides a uniform and structured blood flow to all cell layers, fast-dividing tumor cells often form chaotically organized structures. Cancer blood vessels are, in contrast to normal vessels, dilated, irregularly built (e.g., they may have dead ends) and leaky due to loose contacts of perivascular cells with endotheliocytes [2], [3]. This results, on the one hand, in extravasation of liquids and proteins that build interstitial pressure, and, on the other hand, in insufficient tissue supply with oxygen and nutrients. Thus, due to perfusion issues, tumor cell layers distantly located from the vessels receive inadequate supply of nutrients and have abnormal flow of the metabolites [4]. Taken together, tumors have a unique milieu that cannot be well-tolerated by healthy non-transformed cells. This environment is believed to exert selective pressure on the cells, thus driving propagation of the cells adapted to these harsh conditions.

Specific cancer microenvironment is a cause and a consequence of metabolic re-wiring of both tumor cells and cancer-associated non-transformed cells [5], [6]. While under physiological conditions all systems of an organism (e.g., breathing, excretion) are directed towards maintaining of a slightly alkaline, relatively constant pH, tumor cells shift their metabolism towards alternative pathways that contribute to the acidification of the interstitial space (the phenomenon referred to as tumor acidosis) [7], [8]. Low oxygen pressure within the tumor mass brings about metabolic switch of cancer cells that is characterized by elevated glycolytic activity and, hence, increased lactate production through monocarboxylate transporters (MCTs). Tumor-recruited normal cells were also shown to adapt to the microenvironment conditions through metabolic alterations, in their turn also contributing to the acidification of the extracellular environment. Common molecular hallmarks of tumor-associated metabolism connected to pH regulation are elevated activity and/or expression of proton pumps, carbonic anhydrases and ion channels responsible for the transport of metabolic acids to the extracellular space [9], [10].

It should be noted that local acidic pH often occurs also in a healthy organism. For example, the slightly acidic skin surface is believed to play a protective role against bacterial invasion. Low pH maintenance of the epidermis is achieved by the interplay between focal-adhesion kinases and the Na⁺/H⁺ exchanger type 1 (NHE1) [11], [12]. Besides, physiological inflammatory response is associated with local acidosis, presumably also due to its bacteriostatic effect. In this case, acidic conditions are achieved by protons secreted by macrophages [13], [14]. In a similar way, pH as low as 5.5 is induced in the skeleton via proton secreting osteoclasts during the process of bone resorption [15]. Under all the above-mentioned conditions, tissue acidosis is temporarily and spatially limited whereas tumors have constitutively low pH on their site. A tumor consists of cancer cells as well as recruited normal residing cells that are being exploited to maintain specific homeostasis within a tumor organ. Therefore, normally occurring mechanisms of pH decrease can be encountered within tumors (e.g., tumor-inflammation associated proton secretion by macrophages or osteoclast involvement). Importantly, although proton secretion does take place in tumors, tumor acidosis is achieved through the combination of proton extrusion and the secretion of acidic metabolites by tumor and tumor-associated cells [16].

Tissue samples from patients with head and neck cancer as well as musculoskeletal cancers were shown to be acidic [17], [18], [19]. Moreover, tumor acidosis is regarded as one of the contributing factors to therapy resistance. Partially, this is due to the mutational profile of stress-adapted cells, and, partially, due to the pH-induced modifications that occur to a drug in the extracellular environment. Interestingly, measuring the acidity of a tumor by non-invasive methods proved to predict antitumor activity and the efficiency of a therapy more accurately than the routinely used glucose-uptake imaging with lower tumor acidity correlating with better drug response [20]. Taken together, tumor acidosis is viewed as an important hallmark of cancer that contributes to cancer development, progression and therapy response [21], [22], [23]. In this review article we will try to update the current evidences about the pathogenic role of tumor acidosis and we will specifically discuss how tumor acidosis may negatively affect the efficacy of different therapeutic strategies. Finally, we will identify potential strategies to overcome pH-mediated therapy resistance.