How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression

Elingaard-Larsen, Line O; Rolver, Michala G; Sørensen, Ester E.; Pedersen, Stine Falsig

doi:10.1007/112_2020_23

Cited by 12 publications

(8 citation statements)

References 215 publications

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“…Western blot analysis confirmed the efficacy of both agents (Figure S7 B). Panc02 cells harbor an inactivating SMAD4 mutation, 40 and consistent with the growth‐stimulatory effect of TGFβ in absence of SMAD4 [55], stimulation with TGFβI increased WT control spheroid viability ~4‐fold, while TGFβRI inhibition had no effect under these conditions (Figure 5C,D , left green bars). Remarkably, in WT AA cells, TGFβI had no detectable effect and treatment with SB431542 tended to reduce the already low viability (Figure 5D , left red bars, magnified in Figure 5E ).…”

Section: Resultssupporting

confidence: 73%

“…While heterogeneous extracellular acidosis is an important feature of solid tumors from a wide range of cancers, 12 , 40 pancreas physiology makes acid‐base dysregulation particularly interesting in this organ. Postprandially, massive secretion of HCO 3 − from the epithelial cells to the ducts is accompanied by a corresponding acid flux to the bloodstream to sustain epithelial pH i .…”

Section: Discussionmentioning

confidence: 99%

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Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

Czaplińska

Ialchina

Andersen

et al. 2022

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development.Acid-adaptation-induced gain of cancerous traits was further increased by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt-and Transforming growth factor-β (TGFβ) signaling, as well as expression of the Na + /H + exchanger NHE1,

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

Czaplińska

Ialchina

Andersen

et al. 2022

Intl Journal of Cancer

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“…Tumor-infiltrating immune cells are an important part of the tumor microenvironment. Studies have shown that tumor-infiltrating immune cells can secrete growth factors [ 60 ], inhibit cell apoptosis [ 61 ], promote angiogenesis, and promote tumor growth and metastasis [ 62 ], and the current tumor immune microenvironment has become an important therapeutic target. Our studies displayed that the mRNA expression level of E2F1/2/3/4/7/8 was positively correlated with the level of immune cells infiltration, including B cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Clear Cell Renal Cell Carcinoma

Zhang

Cui

Wang

et al. 2021

Journal of Healthcare Engineering

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Background. E2F transcription factors is a family of transcription factors, and lots of studies have shown that they play a key role in the occurrence and development of many tumors. However, the association between expression, prognostic value, and immune infiltration in the tumor microenvironment of the eight E2Fs members in ccRCC is still unclear. Methods. We used online databases, such as ONCOMINE, UALCAN, Kaplan–Meier plotter, GEPIA, Metascape, TIMER, and cBioPortal, to analyze the effect of mRNA expression of E2Fs family members in ccRCC on the prognosis of patients and the relationship with immune infiltration. Results. Except for E2F5, other seven members of the family of E2Fs mRNA expression levels in ccRCC tissues were significantly higher than control tissues. And the high expression of E2Fs mRNA in ccRCC patients was related to cancer stage and tumor grade. Survival analysis results suggested that elevated mRNA expression levels of E2F1/2/3/4/7/8 were significantly related to the shorter overall survival (OS) in ccRCC patients ( P = 3.9E – 06), while high mRNA expression of E2F6 is not related to OS ( P = 0.061). Mutations of E2Fs were correlated with shorter OS of ccRCC patients ( P = 7.094E – 5). In addition, mRNA expression of E2F1/2/3/4/7/8 was positively correlated with infiltration of six types of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Conclusions. These results indicate that E2F1/2/3/4/7/8 may be used as a prognostic marker for the survival of ccRCC patients and laid the foundation for studying the immune infiltration role of E2Fs family members in tumors.

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“…As noted above, nutrient limitations, hypoxia, oxidative stress, and profound extracellular acidosis are key properties of the tumor microenvironment [ 6 , 160 ], and similar to normal cells, tumor cells respond to such stressors with mitochondrial hyperfusion. One of the first and still most thorough analyses of this phenomenon [ 161 ] showed that when nutrient availability was switched from glucose to galactose/glutamine, HeLa cells developed a hyperfused mitochondrial network that allowed them to derive energy by glutaminolysis.…”

Section: Cancer Cell Functions Driven By Changes In Mitochondrial Architecturementioning

confidence: 99%

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

Pedersen

Flinck

Pardo

2021

IJMS

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Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis.

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How Reciprocal Interactions Between the Tumor Microenvironment and Ion Transport Proteins Drive Cancer Progression

Cited by 12 publications

References 215 publications

Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Clear Cell Renal Cell Carcinoma

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

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