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. 2018 Mar;472(3):395-405.
doi: 10.1007/s00428-017-2263-3. Epub 2017 Nov 13.

Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer

Artur Mezheyeuski  1   2 , Carina Strell  3 , Ina Hrynchyk  4 , Tormod Kyrre Guren  5   6 , Anca Dragomir  7 , Tatyana Doroshenko  8 , Oksana Pashkova  8 , Julia Gorgun  9 , Kseniya Ruksha  10 , Per Pfeiffer  11 , Elin H Kure  12 , Halfdan Sorbye  13 , David Edler  14 , Anna Martling  14 , Bengt Glimelius  15 , Arne Östman  3 , Anna Portyanko  16
Affiliations

Treatment-related survival associations of claudin-2 expression in fibroblasts of colorectal cancer

Artur Mezheyeuski et al. Virchows Arch. 2018 Mar.

Abstract

Claudin-2 is a trans-membrane protein-component of tight junctions in epithelial cells. Elevated claudin-2 expression has been reported in colorectal cancer (CRC). The aim of this study was to investigate the expression patterns of claudin-2 in human CRC samples and analyze its association with clinical characteristics and treatment outcome. TMAs of primary tumors from two cohorts of metastatic CRC (mCRC) were used. Claudin-2 IHC staining was evaluated in a semi-quantitative manner in different regions and cell types. Claudin-2 expression was also analyzed by immunofluorescence in primary cultures of human CRC cancer-associated fibroblasts (CAFs). Initial analyses identified previously unrecognized expression patterns of claudin-2 in CAFs of human CRC. Claudin-2 expression in CAFs of the invasive margin was associated with shorter progression-free survival. Subgroup analyses demonstrated that the survival associations occurred among cases that received 5-FU+oxaliplatin combination treatment, but not in patients receiving 5-FU±irinotecan. The finding was validated by analyses of the independent cohort. In summary, previously unreported stromal expression of claudin-2 in CAFs of human CRC was detected together with significant association between high claudin-2 expression in CAFs and shorter survival in 5-FU+oxaliplatin-treated mCRC patients.

Keywords: Cancer-associated fibroblasts; Cell adhesion; Claudin-2; Colorectal cancer.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Claudin-2 expression in human colorectal cancer tissue. a Representative image of tumor tissue without (upper image) and with high (lower image) claudin-2 expression in cancer cells. Note strong blue staining on pan-cytokeratin (red)-positive areas. b Expression of the claudin-2 in macrophages. Note dark-blue spots with irregular shape, frequently with a blank region in the centre (unstained nucleus). c Dot-like expression of the claudin-2 in cells with fibroblast-like morphology. d Expression of claudin-2, as determined by IF, in a fraction of cells within a primary CAF culture (passage 4). Note claudin-2 dot-like high-level expression in a cell marked “H” and low-level diffuse expression in a cell marked “L” (green) in fraction of CAFs. Red color used for the visualization of α-SMA
Fig. 2
Fig. 2
Associations between claudin-2 and progression-free survival (PFS). Kaplan–Meier graphs showing associations in the SPCRC cohort between PFS and claudin-2 expression in stromal cell/CAFs (a). Results from analyses of 5FU+oxaliplatin subgroup are shown in b. Results are shown separately for expression in central tumor (CT) (left panel) or invasive margin (IM) (right panel). HRs from Cox regression analyses, including confidence intervals, and p values are indicated for all analyses. Note, according to Bonferrony correction for the statistical significance, p value = 0.005 shall be considered as the threshold in the current illustration
Fig. 3
Fig. 3
Associations between stromal/CAF-associated claudin-2 expression and PFS in the NORDIC-VII cohort. Kaplan–Meier graphs showing associations in the NORDIC-VII cohort between PFS and claudin-2 expression in cancer cells (a) or in stromal cell/CAFs (b)
See this image and copyright information in PMC

References

    1. Ahmad R, Chaturvedi R, Olivares-Villagomez D, Habib T, Asim M, Shivesh P, Polk DB, Wilson KT, Washington MK, Van Kaer L, Dhawan P, Singh AB. Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal Immunol. 2014;7:1340–1353. doi: 10.1038/mi.2014.21. - DOI - PMC - PubMed
    1. Baranowska-Kortylewicz J, Abe M, Pietras K, Kortylewicz ZP, Kurizaki T, Nearman J, Paulsson J, Mosley RL, Enke CA, Ostman A. Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy. Cancer Res. 2005;65:7824–7831. doi: 10.1158/0008-5472.CAN-04-3991. - DOI - PMC - PubMed
    1. Baxter LT, Jain RK. Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection. Microvasc Res. 1989;37:77–104. doi: 10.1016/0026-2862(89)90074-5. - DOI - PubMed
    1. Elferink MA, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JH. Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands. Int J Color Dis. 2015;30:205–212. doi: 10.1007/s00384-014-2085-6. - DOI - PubMed
    1. Garcia-Godinez A, Contreras RG, Gonzalez-Del-Pliego M, Aguirre-Benitez E, Acuna-Macias I, de la Vega MT, Martin-Tapia D, Solano-Agama C, Mendoza-Garrido ME. Anterior and intermediate pituitary tissues express claudin 4 in follicle stellate cells and claudins 2 and 5 in endothelial cells. Cell Tissue Res. 2014;357:309–321. doi: 10.1007/s00441-014-1827-7. - DOI - PubMed

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