Upregulated Na+/H+-Exchange Protects Human Colon Cancer Tissue against Intracellular Acidification

Increased metabolism accelerates local acid production in cancer tissue. The mechanisms eliminating acidic waste products from human colon cancer tissue represent promising therapeutic targets for pharmacological manipulation in order to improve prognosis for the increasing number of patients with colon cancer. We sampled biopsies of human colonic adenocarcinomas and matched normal colon tissue from patients undergoing colon cancer surgery. We measured steady-state intracellular pH and rates of net acid extrusion in freshly isolated human colonic crypts based on fluorescence microscopy. Net acid extrusion was almost entirely (>95%) Na+-dependent. The capacity for net acid extrusion was increased and steady-state intracellular pH elevated around 0.5 in crypts from colon cancer tissue compared with normal colon tissue irrespective of whether they were investigated in the presence or absence of CO2/HCO3–. The accelerated net acid extrusion from the human colon cancer tissue was sensitive to the Na+/H+-exchange inhibitor cariporide. We conclude that enhanced net acid extrusion via Na+/H+-exchange elevates intracellular pH in human colon cancer tissue.

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Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00368.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. H245-H254 ◽

Cited By ~ 3

Author(s):

Ninna C. S. Voss ◽

Henrik Kold-Petersen ◽

Ebbe Boedtkjer

Keyword(s):

Nitric Oxide ◽

Colon Cancer ◽

Human Colon ◽

No Synthase ◽

Cancer Tissue ◽

Solid Cancer ◽

Tumor Perfusion ◽

Normal Colon ◽

Human Colon Cancer ◽

Feed Arteries

Inadequate perfusion of solid cancer tissue results in low local nutrient and oxygen levels and accumulation of acidic waste products. Previous investigations have focused primarily on tumor blood vessel architecture, and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistance-sized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared with normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO synthase expression are increased in colon cancer feed arteries compared with normal colon arteries, whereas vasorelaxation to exogenous NO donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO synthase inhibition. Rhythmic oscillations in vascular tone, known as vasomotion, are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. NEW & NOTEWORTHY Local vascular resistance influences tumor perfusion. Arteries supplying human colonic adenocarcinomas show enhanced vasorelaxation and reduced vasocontraction mainly due to elevated nitric oxide-mediated signaling. Rhythmic oscillations in tone, known as vasomotion, are attenuated in colon cancer feed arteries.

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Abstract 5166: Gene expression microarray analysis identifies association of genes in the integrin/fak signaling pathway with claudin-7 in human colon cancer tissue

10.1158/1538-7445.am2016-5166 ◽

2016 ◽

Cited By ~ 1

Author(s):

Lu Kong ◽

Lei Ding

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Signaling Pathway ◽

Human Colon ◽

Cancer Tissue ◽

Gene Expression Microarray ◽

Expression Microarray ◽

Colon Cancer Tissue ◽

Human Colon Cancer ◽

Gene Expression Microarray Analysis

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Resistance factors in colon cancer tissue and the adjacent normal colon tissue: glutathione S-transferases α and π, glutathione and aldehyde dehydrogenase

Cancer Letters ◽

10.1016/s0304-3835(98)00059-7 ◽

1998 ◽

Vol 128 (1) ◽

pp. 105-112 ◽

Cited By ~ 18

Author(s):

Jan Georg Hengstler ◽

Thomas Böttger ◽

Berno Tanner ◽

Britta Dietrich ◽

Michael Henrich ◽

...

Keyword(s):

Colon Cancer ◽

Aldehyde Dehydrogenase ◽

Cancer Tissue ◽

Normal Colon ◽

Colon Tissue ◽

Colon Cancer Tissue ◽

Resistance Factors ◽

Normal Colon Tissue ◽

Glutathione S Transferases

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Surface-Enhanced Raman Scattering Spectroscopic Assay of Immunohistochemically Stained Human Colon Cancer Tissue

Chinese Journal of Lasers ◽

10.3788/cjl201138.0904001 ◽

2011 ◽

Vol 38 (9) ◽

pp. 0904001

Author(s):

席刚琴 Xi Gangqin ◽

陈燕坪 Chen Yanping ◽

陈刚 Chen Gang ◽

郑雄伟 Zheng Xiongwei ◽

冯尚源 Feng Shangyuan ◽

...

Keyword(s):

Colon Cancer ◽

Raman Scattering ◽

Human Colon ◽

Surface Enhanced Raman Scattering ◽

Cancer Tissue ◽

Colon Cancer Tissue ◽

Human Colon Cancer ◽

Surface Enhanced ◽

Surface Enhanced Raman ◽

Enhanced Raman Scattering

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BNIP3L (Nix) expression in colon cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15097 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15097-e15097

Author(s):

J. E. Littlejohn ◽

D. Jupiter ◽

X. Cao ◽

L. Zhang ◽

M. Shabahang ◽

...

Keyword(s):

Colon Cancer ◽

Human Colon ◽

Mrna Levels ◽

Normal Colon ◽

Colon Tissue ◽

Human Colon Cancer ◽

Variable Expression ◽

Colon Tumors ◽

Normal Colon Tissue ◽

Protein Levels

e15097 Background: Microenvironmental adaptation to hypoxic conditions is critical for a cell to survive in a growing solid tumor. BNIP3L (Nix) mediates apoptosis during hypoxia in cancer cell lines, and Nix knockdown promotes tumor growth in-vivo through decreased apoptosis and increased proliferation, suggesting a means by which cells can adapt. Little is known specifically about Nix expression and its importance in human colon cancer. To gain insight into expression of this gene in colon tumors, the present study analyzed mRNA microarray data from 227 colon tumors and 22 normal colon tissue samples and queried differential expression of Nix. These results were compared to the protein levels present in human colon tumors. Methods: mRNA expression of 227 human colon tumors (made available by the Expression Project for Oncology (expO)) and 22 normal colon samples (retrieved from the Gene Expression Omnibus (GEO)) was analyzed. These samples were hybridized to the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array, assaying 17,726 NCBI Entrez genes. Immunohistochemistry was performed on human tissue microarray CO701 (US Biomax, Inc.) containing 62 tumor samples. Results: Nix mRNA levels were shown to increase from normal to cancer (log-fold change of 0.961, Benjamini-Hochberg FDR adjusted p < 0.001). IHC demonstrated variable levels of Nix present in colon tumors: 38/62 (61.3%) of tumors stained positive for Nix while 24/62 (38.7%) were negative. Conclusions: We have shown that mRNA levels of Nix are upregulated in the transition from normal colon tissue to cancer but that protein levels in tumors demonstrate variable expression. This suggests that silencing of Nix occurs at various stages of tumorigenic progression and results in isolated populations of cells within a growing tumor that are uniquely resistant to apoptosis. Better understanding of Nix in the context of a growing colon tumor is needed and could lead to development of more successful therapeutics. No significant financial relationships to disclose.

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