The acidic microenvironment as a possible niche of dormant tumor cells

Peppicelli, Silvia; Andreucci, Elena; Ruzzolini, Jessica; Laurenzana, Anna; Margheri, Francesca; Fibbi, Gabriella; Rosso, Mario Del; Bianchini, Francesca; Calorini, Lido

doi:10.1007/s00018-017-2496-y

Cited by 94 publications

(64 citation statements)

References 112 publications

(121 reference statements)

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“…Acidosis, a biochemical hallmark of solid tumors, plays essential role in tumor progression. The effects of acidosis on solid tumors can be summarized as follows: 1) promoting cell invasion and metastasis; 2) inducing autophagy and reducing apoptosis; 3) leading to metabolism shift; 4) enhancing angiogenesis [22,23]; 5) favoring escape from immune surveillance; 6) stimulating resistance to radiotherapy or chemotherapy [24]. Moreover, the acidic environment of solid tumors has recently been proposed to provide a niche for dormant cells based on these features [24].…”

Section: Discussionmentioning

confidence: 99%

“…The effects of acidosis on solid tumors can be summarized as follows: 1) promoting cell invasion and metastasis; 2) inducing autophagy and reducing apoptosis; 3) leading to metabolism shift; 4) enhancing angiogenesis [22,23]; 5) favoring escape from immune surveillance; 6) stimulating resistance to radiotherapy or chemotherapy [24]. Moreover, the acidic environment of solid tumors has recently been proposed to provide a niche for dormant cells based on these features [24]. The present study showed that the acid-adapted SW620 cells have stronger tumorigenicity in subcutaneous transplantation model, which is consistent with a previous study showing that the acid adapted breast cancer cells grow faster in vivo [17].…”

Section: Discussionmentioning

confidence: 99%

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Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

et al. 2019

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Song He (2019) Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells, Cell Cycle, 18:4, 511-522, ABSTRACTThe acidic extracellular microenvironment, namely acidosis, is a biochemical hallmark of solid tumors. However, the tumorigenicity, metastatic potential, gene expression profile and chromatin accessibility of acidosis-adapted colorectal cancer cells remain unknown. The colorectal cancer cell SW620 was cultured in acidic medium (pH 6.5) for more than 3 months to be acidosis-adapted (SW620-AA). In comparison to parental cells, SW620-AA cells exhibit enhanced tumorigenicity and liver metastatic potential in vivo. Following mRNA and lncRNA expression profiling, we validated that OLMF1, NFIB, SMAD9, DGKB are upregulated, while SESN2, MAP1B, UTRN, PCDH19, IL18, LMO2, CNKSR3, GXYLT2 are downregulated in SW620-AA cells. The differentially expressed mRNAs were significantly enriched in DNA remodeling-associated pathways including HDACs deacetylate histones, SIRT1 pathway, DNA methylation, DNA bending complex, and RNA polymerase 1 chain elongation. Finally, chromatin accessibility evaluation by ATAC-sequencing revealed that the differentially opened peaks were enriched in pathways such as small cell lung cancer, pathways in cancer, ErbB signaling, endometrial cancer, and chronic myeloid leukemia, which were mainly distributed in intergenic regions and introns. These results suggest that the chromatin accessibility changes are correlated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

et al. 2019

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“…Hence, hypoxia triggers several events such as metabolic reprogramming of tumour cells, and modulation of tumour microenvironment (TME) that results in the rearrangement of extracellular matrix and formation of new faulty and leaky vessels, which may lead to metastasis 11 . In order to survive in an oxygen deficient environment, tumour cells reprogramme their metabolism to an anaerobic glycolysis resulting in the intracellular accumulation of lactic and carbonic acid [12][13][14][15][16] . To avoid the toxic intracellular acidification, tumour cells potentiate the expression of extrusion mechanisms, including monocarboxylate transporters and proton flux regulators, such as vacuolar H þ -ATPases, Na þ /H þ exchanger, Na þ /HCO 3 co-transporter and carbonic anhydrase (CA) IX [17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

Ruzzolini

Laurenzana

Andreucci

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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& Lido Calorini (2020) A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer, ABSTRACTThe emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 affects cell viability and colony forming capability to greater extent than either treatment alone of breast, colorectal and melanoma cancer cells. At the molecular level, this therapeutic regimen resulted in a synergistically increase of histone H4 and p53 acetylation in all tested cell lines. Overall, our findings showed that SAHA and SLC-0111 can be regarded as very attractive combination providing a potential therapeutic strategy against different cancer models. ARTICLE HISTORY

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“…Healthy and tumor cells present different regulations of extra‐ and intracellular pH values which may influence TMZ PK although this has not been studied mechanistically up to our knowledge. Cancer cells can acidify their micro‐environment which may favor the development of resistant clones, promote tumor invasion and suppress the antitumor immune response . Furthermore, cancer cells may present an abnormal regulation of their intracellular pH which allow them to evade from acid‐mediated toxicities whereas healthy cells would not survive in acidic environment .…”

Section: Introductionmentioning

confidence: 99%

“…Cancer cells can acidify their micro-environment which may favor the development of resistant clones, promote tumor invasion and suppress the antitumor immune response. [7][8][9] Furthermore, cancer cells may present an abnormal regulation of their intracellular pH which allow them to evade from acid-mediated toxicities whereas healthy cells would not survive in acidic environment. 10,11 Several anticancer strategies currently under development rely on targeting the tumor pH such as the administration of proton pump inhibitors to invert extracellular/intracellular pH gradient or the design of pHcontrolled nanoparticles releasing the active compound at acid pH.…”

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confidence: 99%

pH as a potential therapeutic target to improve temozolomide antitumor efficacy : A mechanistic modeling study

Stéphanou

Ballesta

2019

Pharmacology Res & Perspec

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Despite intensive treatments including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. A systems pharmacology approach was undertaken to investigate TMZ pharmacokinetics‐pharmacodynamics (PK‐PD) incorporating the effect of local pH, tumor spatial configuration and micro‐environment. A hybrid mathematical framework was designed coupling ordinary differential equations describing the intracellular reactions, with a spatial cellular automaton to individualize the cells. A differential drug impact on tumor and healthy cells at constant extracellular pH was computationally demonstrated as TMZ‐induced DNA damage was larger in tumor cells as compared to normal cells due to less acidic intracellular pH in cancer cells. Optimality of TMZ efficacy defined as maximum difference between damage in tumor and healthy cells was reached for extracellular pH between 6.8 and 7.5. Next, TMZ PK‐PD in a solid tumor was demonstrated to highly depend on its spatial configuration as spread cancer cells or fragmented tumors presented higher TMZ‐induced damage as compared to compact tumor spheroid. Simulations highlighted that smaller tumors were less acidic than bigger ones allowing for faster TMZ activation and their closer distance to blood capillaries allowed for better drug penetration. For model parameters corresponding to U87 glioma cells, inter‐cell variability in TMZ uptake play no role regarding the mean drug‐induced damage in the whole cell population whereas this quantity was increased by inter‐cell variability in TMZ efflux which was thus a disadvantage in terms of drug resistance. Overall, this study revealed pH as a new potential target to significantly improve TMZ antitumor efficacy.

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The acidic microenvironment as a possible niche of dormant tumor cells

Cited by 94 publications

References 112 publications

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

Chromatin accessibility changes are associated with enhanced growth and liver metastasis capacity of acid-adapted colorectal cancer cells

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

pH as a potential therapeutic target to improve temozolomide antitumor efficacy : A mechanistic modeling study

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