Review Article | Open Access
Effects of tumor microenvironment acidification on progression of pancreatic ductal adenocarcinoma: A reviewManh Tien Tran1
1Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. Correspondence: Manh Tien Tran (Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan; E-mail: firstname.lastname@example.org).
Asia-Pacific Journal of Oncology 2021, 2: 27-34. https://doi.org/10.32948/ajo.2021.08.14
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression and profound resistance to treatment. It has been best characterized that tumor microenvironment such as hypoxia and nutrient deprivation contributes to cancer progression; however, the role of tumor microenvironment acidification (TMA), a major feature of tumor tissue, has not been intensively studied. Interestingly, clinicopathological clues have recently unraveled that TMA is involved in promoting cancer progression although the exact signaling pathways is poorly understood. In PDAC, the TAM is tightly regulated by proton (H+) transporters and pumps. This review dissects and summarizes the roles of these H+-extruding regulators in facilitating PDAC progression.
Key words H+ transporters, H+ pumps, TMA, PDAC
The pancreas is a complicated organ consisted of both exocrine glands (acinar and ductal cells secreting digestive enzymes into the intestinal lumen) and endocrine (α, β, δ, ε) glands, also known as the islets of Langerhans, which are responsible for secreting hormones into the blood stream . Under certain extracellular stimuli such as tissue damage, stress conditions, or inflammatory factors, acinar cells can transdifferentiate into cells expressing specific ductal markers [8-10]. During acinar-to-ductal metaplasia (ADM), acinar cells acquire ‘progenitor cell-like’ properties that render them more susceptible to pro-oncogenic hits, such as activating mutations in the proto-oncogene Kirsten rat sarcoma virus (KRAS), eventually transforming them into pancreatic intra-epithelial neoplasias (PanINs). This transformation is generally considered as the initial step in PDAC development followed by sequential progression involving genetic hits in several tumor suppressor genes. Many studies have indicated that the gene encoding the proto-oncogenic GTPase KRAS as well as several tumor suppressor genes, consisting of tumor suppressor p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homologue 4 (SMAD4), exhibit the most frequent alterations and/or mutations in PDAC [11, 12]. Besides, RAC-beta serine/threonine-protein kinase (AKT2) is frequently overexpressed [13, 14], and the activity of its upstream regulator phosphoinositide 3-kinase (PI3K) is often enhanced in PDAC, which leads to increased cancer cell survival [15, 16].
The PDAC tumor microenvironment (TME) is principally consisted of various cell types such as fibroblasts, endothelial cells, neurons, and infiltrating immune cells as well as the extracellular matrix (ECM) proteins such as cytokines, growth factors and blood vessels. The majority of the PDAC histology is desmoplasia derived from the stroma/desmoplastic reactions. The interactions amongst components in TME and the cancer cells play a central role in facilitating immune escape, tumor progression, and metastasis. The major characteristics of TME include hypoxia, nutrient deprivation and extracellular acidification that are thought to be the potential activators of cancer progression and metastasis. Whereas hypoxia and nutrient deprivation have been well-documented, TMA in PDAC has not been intensively studied. However, recent studies have confirmed that TAM is involved in initiating the early events of malignant transformation [17-20]; more crucially, promoting tumor progression and metastasis. In the context of TMA-mediated cancer progression, it is well known that invasiveness and metastasis of cancer cells are accelerated by a variety of extracellular proteases such as metalloproteinases (MMPs), thiol proteases, serine proteases and acid proteases, which are responsible for degrading the tumor barriers, creating ideal condition to favor tumor metastasis. Notably, the proteolytic activity of these enzymes could be optimized in the TMA.
Cancer cells exert aerobic glycolysis to generate energy and supply intermediates for macromolecule biosynthetic that are required for cell survival, differentiation and proliferation . A common by-product generated by this metabolic pathway is lactate, which is converted from pyruvate by lactic acid dehydrogenase-A (LDHA) . The cytosolically accumulated lactate is extruded into the TME via activated H+-linked monocarboxylate transporters (MCTs), subsequently acidifying TME . Lactate activates vascular endothelial growth factor (VEGF) , transforming growth factor beta (TGFβ) , interleukin-1 (IL-1)  and HIF-1 . Also, it is worth noting that glycolytic inactivation in cancer cells still facilitates acidification of the TME [28-30], indicating that the H+ efflux pathways might be regulated by other H+ extruders, in addition to MCTs, which include Na+/H+ exchangers (NHEs) [31, 32], sodium/bicarbonate transporters (NBCs) , V-type H+ ATPases [34, 35], and carbonic anhydrases (CAs) . Therefore, addressing the question of why cancer cells, but not normal, non-transformed cells, can thrive in the TME is of utmost importance since therapies interfering with the TME might provide useful clinical strategies for patients with cancer. This review will summarize the specific roles of H+ transporters, pumps and channels in facilitating the PDAC development and progression.
Alternatively, lactate discharging might be mediated through gap junctions that are connected by connexin channels. Previously Dovmark et al. demonstrated that Cx43 channels played a role as the crucial conduits for transmitting lactate from glycolytic PDAC cells into the neighboring cells, which triggers alkalization of recipient cells . Markedly, cell-cell contact via this junctional flux is thermodynamically insensitive to TME, which possibly compensates for the TME-induced reduction of MCT activity. PDAC tumors are characterized by profoundly under-perfused regions requiring efficient mechanisms for discharging and transmitting lactate across clusters of PDAC cells , towards specific regions that possess the most favorable transmembrane gradient for MCT-assisted off-loading lactate. Due to it, the junctional flux of lactate benefits tumor growth through (1) providing an extracellular pH (pHe)-insensitive route for discharging metabolic wastes from glycolytic PDAC cells, and (2) alkalizing neighboring cells such as fibroblasts. It is suggested that blocking Cx43 channels by the specific blocker such as inoxynil and ioxynil octanoate might be a promising strategy to inhibit PDAC progression. However, more in vivo experiments using animal models are needed to test the anti-cancer efficaciousness of these specific blockers of Cx43 channels.
Besides, other NHE isoforms, such as NHE6 and NHE9, have also been confirmed to be essential for tumor pH regulation, carcinogenesis, and development of chemoresistance [55, 56]. NHE7 localized in the trans-Golgi network (TGN) played a role in acidifying the TGN and controlling pHi in PDAC cells . NHE7 was up-regulated in PDAC tumors, and correlated with poor prognosis and patient survival .
Additionally, conversion of CO2 to HCO3- and H+ is catalyzed by CAs that are the transmembrane zinc metallo-enzymes. In mammals, there are five cytosolic forms (CA I, CA II, CA III, CA VII, and CA XIII), five membrane-bound enzymes (CA IV, CA IX, CA XII, CA XIV, and CA XV), two mitochondrial forms (CA VA and CA VB), and a secreted CA isozyme (CA VI) . Among CA isoforms, CA IX is best characterized to be critical for regulating pHi  and acidifying extracellular environment . CA IX is tightly associated with promotion of the aggressive/invasive phenotype of tumors ; importantly, it was identified to be a prominent biomarker of poor patient prognosis for many solid cancers . CA IX that was activated by the HIF-1α pathways under hypoxic conditions played an important role in maintaining the hypoxic tumor microenvironment, which promoted tumor growth . Structurally, CA IX consisting of an N-terminal proteoglycan-like domain, a CA domain, a transmembrane anchor that is associated with plasma membrane via a single-pass transmembrane region, and a C-terminal cytoplasmic tail, is responsible for ameliorating the CO2 hydration as well as accelerating CO2 diffusion and H+ mobility in the tumor tissue. Moreover, it was demonstrated that CA IX spatially and functionally cooperated with a variety of acid extruders and HCO3- transporters such as NBCe1-B, NBCn1 [69-71], and/or lactate and H+-exporting MCT1, MCT4, and NHE1 . Recently, CA IX has recently been identified to be a pro-migratory factor facilitating cell movement and invasion by weakening intercellular adhesion and increasing cell dissociation via alleviating E-cadherin binding to β-catenin [70, 73]. In PDAC, McDonald et al. revealed an important role of CA IX in mediating the survival of pancreatic cancer cells by modulating pHi and glycolysis under hypoxic conditions . Furthermore, Yuji Li et al. reported that knockdown of CA IX expression markedly inhibited the invasiveness and metastasis of PDAC cells lines (AsPC-1 and Miacapa), suggesting a pro-tumorigenic role of CA IX in initiating the PDAC progression . Together, blocking the functional roles of CA IX might be an up-and-coming solution to alleviate the PDAC development and progression.
In the context of cancer, plasma membrane V-ATPases are necessary to maintain not only an alkaline intracellular environment that is favorable for cancer cell growth, but also an acidic extracellular environment that favors cancer cell invasion . Specifically, the elevated expression levels of plasma membrane V-ATPases were found in metastatic breast cancer cells , and blocking V-ATPases by specific inhibitors such as bafilomycin and concanamycin A (ConA) diminished the invasiveness of these cells in a manner proposed to involve plasma membrane-localized V-ATPases. Interestingly, the similar effects of blockade of V-ATPase activity were observed in melanoma cells  and prostate cancer cells [86, 87].
V-ATPase function is of particular interest in PDAC, given the reliance of this exceptionally aggressive cancer on nutrient scavenging, and increased lysosomal catabolism, processes critically dependent on V-ATPase activity. In PDAC patient tissues, expression levels of V-ATPase subunits V1E and V0c were correlated with cancer stage. Nonetheless, contrary to what was found in other cancer cells, V-ATPase inhibition did not consistently weaken the invasiveness of PDAC cells. Concanamycin-induced blockade of V-ATPase activity enhanced MMP2 activity, but weakened MMP9 activity ; however, in general, the inhibition of V-ATPase activity alleviated the invasiveness of PDAC cells . Furthermore, V-ATPase activity is confirmed to be essential for degrading MT-MMP [89, 90], which was important for promoting the invasiveness of PDAC cells [91, 92]. Hayashi et al. previously reported that vacuolar V-ATPases was essential for regulating the transport of H+ from cytosol into endocytic organelles and secretory vesicles, which are responsible for transporting H+ through plasma membrane , indicating an important role of vacuolar V-ATPases in promoting extracellular acidification in PDAC cells. However, more studies are needed to reveal all aspects of functional roles of V-ATPases in regulating PDAC progression before establishing the drug program development that targets V-ATPases for treatment of patients with pancreatic cancer.
In total, I have presented the major effects of the TMA on facilitating progression of PDAC, indicating that TMA may be considered as a hallmark of PDAC. In fact, the current mechanisms underlying the TMA-mediated regulation of PDAC progression is poorly understood, and thus, more in-depth studies should be conducted to improve our knowledge of the relationship between the TMA and PDAC. This, in turn, may open a therapeutic window for pancreatic cancer treatments. In this review, the roles of H+ transporters (NHEs, NBCs, and MCTs) and pumps (V-ATPases) in facilitating the TMA by providing the optimal conditions for MMP degradation in the ECM, may play a critical role in the invasiveness of PDAC cells (Figure 1). Therefore, blockade of such H+ regulators by the specific blockers would be a promising approach that may provide a possible treatment for patients with pancreatic cancer.
No research involving experimentation on human or animal subjects was conducted.
The author contributed solely to the work.
The author declares no conflict of interest with the work.
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