Alternating pH landscapes shape epithelial cancer initiation and progression: Focus on pancreatic cancer

Abstract

We present here the hypothesis that the unique microenvironmental pH landscape of acid-base transporting epithelia is an important factor in development of epithelial cancers, by rendering the epithelial and stromal cells pre-adapted to the heterogeneous extracellular pH (pH ) in the tumor microenvironment. Cells residing in organs with net acid-base transporting epithelia such as the pancreatic ductal and gastric epithelia are exposed to very different, temporally highly variable pH values apically and basolaterally. This translates into spatially and temporally non-uniform intracellular pH (pH ) patterns. Disturbed pH - and pH -homeostasis contributes to essentially all hallmarks of cancer. Our hypothesis, that the physiological pH microenvironment in acid-base secreting epithelia shapes cancers arising in these tissues, can be tested using novel imaging tools. The acidic tumor pH in turn might be exploited therapeutically. Pancreatic cancers are used as our prime example, but we propose that this concept is also relevant for other cancers of acid-base transporting epithelia.

Cutaneous pH landscape as a facilitator of melanoma initiation and progression

“…Yet, the physiological pH microenvironment of the host organ and pH‐dependent steps of cancer initiation have by and large been neglected so far. Considering the extreme pH values and the enormous acid‐base fluxes, the progenitor cells of some highly aggressive tumours, such as pancreatic or gastric cancer, are physiologically exposed to, raises the question to what extent the pH microenvironment of the host organ contributes to the later phenotype . Superficial skin layers, from where melanoma cells originate, are also characterized by remarkable pH gradients.…”

“…Those are needed because (i) melanoma incidence has dramatically risen over the last 3 decades, (ii) it causes the majority of skin cancer‐related deaths and (iii) even modern immune checkpoint therapies fail in most cases due to intrinsic or acquired resistance . Incorporating our knowledge about the characteristic pH microenvironment and its changes during melanoma progression may ultimately complement current treatment strategies or even be the cornerstone for new therapeutic concepts …”

Roles of pH in control of cell proliferation

“…Well‐studied examples include the prolactin receptor and the EGFR, both important regulators of cell proliferation. Numerous ion channels, not limited to the H + ‐gated acid‐sensing ion channels (ASICs), are sensitive to pH e in the physiological range . This establishes a link between pH e and, for example V m and [Ca 2+ ] i –important regulators of proliferation (see below).…”

“…V m changes during cell cycle progression in large part reflect changes in K + channel expression and activity, observed for several classes of K + channels . Notably, these channels are often highly sensitive to both pH i and pH e . It is therefore tempting to speculate that acid/base transport proteins may exert their effect on cell cycle progression by altering K + ‐channel activity and thus V m (Figure ).…”

A Tribute to Paul H. Guth, MD (1927–2017)

“…Along the way, Paul published in 1963 one of the first papers describing the effects of restraint stress on gastric ulceration [7], forming the basis for the most-used model of stress-induced gastrointestinal injury, which has been studied in numerous organs exposed to ischemic, inflammatory, and other forms of stress. He also adopted his in vivo microcirculation model to the measurement of intracellular pH using trapped intracellular pH-sensitive fluorescence dyes [8], forming the basis of the first measurements of intracellular pH in the epithelial cells of living animals [9], later adapted clinically to the technique of fluorescent endoscopy [10]. His output, measured in terms of full-length publications, abstracts, presentations, and grants, identified him as a world leader in foregut mucosal defense mechanisms.…”