Normoxic cells remotely regulate the acid‐base balance of cells at the hypoxic core of connexin‐coupled tumor growths

Dovmark, Tobias H.; Hulı́ková, Alžbeta; Niederer, Steven A.; Vaughan‐Jones, Richard D.; Swietach, Pawel

doi:10.1096/fj.201700480r

Cited by 23 publications

(27 citation statements)

References 34 publications

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“…Such coupling would result in syncytial behaviors of clusters of cells, but the relevance of this to cancer is likely to be limited to special cases, because gap junctional coupling tends to be low or absent in tumors [70], possibly due to the tumor-suppressing effect that has been attributed to connexins [71,72]. Nonetheless, there are cases of well-coupled cancer cells, and in such instances, pH regulation would operate in a syncytial mode [73,74]. Some key points borne from the analyses presented herein are paraphrased below:…”

Section: Discussionmentioning

confidence: 99%

What is pH regulation, and why do cancer cells need it?

Swietach¹

2019

Cancer Metastasis Rev

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Metabolism is a continuous source of acids. To keep up with a desired metabolic rate, tumors must establish an adequate means of clearing their acidic end-products. This homeostatic priority is achieved by various buffers, enzymes, and transporters connected through the common denominator of H + ions. Whilst this complexity is proportionate to the importance of adequate pH control, it is problematic for developing an intuition for tracking the route taken by acids, assessing the relative importance of various acidhandling proteins, and predicting the outcomes of pharmacological inhibition or genetic alteration. Here, with the help of a simplified mathematical framework, the genesis of cancer pH regulation is explained in terms of the obstacles to efficient acid venting and how these are overcome by specific molecules, often associated with cancer. Ultimately, the pH regulatory apparatus in tumors must (i) provide adequate lactic acid permeability through membranes, (ii) facilitate CO 2 /HCO 3 − /H + diffusivity across the interstitium, (iii) invest in a form of active transport that strikes a favorable balance between intracellular pH and intracellular lactate retention under the energetic constraints of a cell, and (iv) enable the necessary feedback to complete the homeostatic loop. A more informed and quantitative approach to understanding acid-handling in cancer is mandatory for identifying vulnerabilities, which could be exploited as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

What is pH regulation, and why do cancer cells need it?

Swietach¹

2019

Cancer Metastasis Rev

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“…Additional reports also indicate that hypoxia modulates Cx43 and GJIC in other cancer types. For example, it has been shown that hypoxia induces Cx43 expression and GJIC in pancreatic ductal adenocarcinoma cells, promoting tumor progression by different metabolic cell coupling-mediated mechanisms [ 55 , 56 ]. We have previously identified that the pre-incubation of melanoma cells to hypoxic conditions, decreases their susceptibility to NK cell cytotoxic attack by interfering with Cx43-GJICs via autophagy-mediated Cx43 degradation at the cytotoxic immunological synapse [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

Tittarelli

Navarrete

Lizana

et al. 2020

IJMS

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Alterations in microRNA (miRNA) profiles, induced by tumor microenvironment stressors, like hypoxia, allow cancer cells to acquire immune-resistance phenotypes. Indeed, hypoxia-induced miRNAs have been implicated in cancer progression through numerous cancer cell non-autonomous mechanisms, including the direct transfer of hypoxia-responsive miRNA from cancer to immune cells via extracellular vesicles. Connexin-43 (Cx43)-constituted gap junctions (GJs) have also been involved in miRNA intercellular mobilization, in other biological processes. In this report, we aimed to evaluate the involvement of Cx43-GJs in the shift of miRNAs induced by hypoxia, from hypoxic melanoma cells to dendritic cells and melanoma-specific cytotoxic T lymphocytes (CTLs). Using qRT-PCR arrays, we identified that miR-192-5p was strongly induced in hypoxic melanoma cells. Immune cells acquired this miRNA after co-culture with hypoxic melanoma cells. The transfer of miR-192-5p was inhibited when hypoxic melanoma cells expressed a dominant negative Cx43 mutant or when Cx43 expression was silenced using specific short-hairpin RNAs. Interestingly, miR-192-5p levels on CTLs after co-culture with hypoxic melanoma cells were inversely correlated with the cytotoxic activity of T cells and with ZEB2 mRNA expression, a validated immune-related target of miR-192-5p, which is also observed in vivo. Altogether, our data suggest that hypoxic melanoma cells may suppress CTLs cytotoxic activity by transferring hypoxia-induced miR-192-5p through a Cx43-GJs driven mechanism, constituting a resistance strategy for immunological tumor escape.

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“…3 ) ions to balance their proton surplus in the hypoxic centerpiece of tumor growth via the so-called connexin (gap-junction protein) -composited "communicating" transitions (142)(143)(144).…”

Section: The Influence Of Tumor Microenvironment On Early Malignancymentioning

confidence: 99%

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

2020

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Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO 2 , and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

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Normoxic cells remotely regulate the acid‐base balance of cells at the hypoxic core of connexin‐coupled tumor growths

Cited by 23 publications

References 34 publications

What is pH regulation, and why do cancer cells need it?

What is pH regulation, and why do cancer cells need it?

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

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