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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells

Authors: Erika Durinikova, Zuzana Kozovska, Martina Poturnajova, Jana Plava, Zuzana Cierna, Andrea Babelova, Roman Bohovic, Silvia Schmidtova, Miroslav Tomas, Lucia Kucerova, Miroslava Matuskova

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Efficiency of colorectal carcinoma treatment by chemotherapy is diminished as the resistance develops over time in patients. The same holds true for 5-fluorouracil, the drug used in first line chemotherapy of colorectal carcinoma.

Methods

Chemoresistant derivative of HT-29 cells was prepared by long-term culturing in increasing concentration of 5-fluorouracil. Cells were characterized by viability assays, flow cytometry, gene expression arrays and kinetic imaging. Immunomagnetic separation was used for isolation of subpopulations positive for cancer stem cells-related surface markers. Aldehyde dehydrogenase expression was attenuated by siRNA. In vivo studies were performed on SCID/bg mice.

Results

The prepared chemoresistant cell line labeled as HT-29/EGFP/FUR is assigned with different morphology, decreased proliferation rate and 135-fold increased IC50 value for 5-fluorouracil in comparison to parental counterparts HT-29/EGFP. The capability of chemoresistant cells to form tumor xenografts, when injected subcutaneously into SCID/bg mice, was strongly compromised, however, they formed distant metastases in mouse lungs spontaneously. Derived cells preserved their resistance in vitro and in vivo even without the 5-fluorouracil selection pressure. More importantly, they were resistant to cisplatin, oxaliplatin and cyclophosphamide exhibiting high cross-resistance along with alterations in expression of cancer-stem cell markers such as CD133, CD166, CD24, CD26, CXCR4, CD271 and CD274. We also detected increased aldehyde dehydrogenase (ALDH) activity associated with overexpression of specific ALDH isoform 1A3. Its inhibition by siRNA approach partially sensitized cells to various agents, thus linking for the first time the ALDH1A3 and chemoresistance in colorectal cancer.

Conclusion

Our study demonstrated that acquired chemoresistance goes along with metastatic and migratory phenotype and can be accompanied with increased activity of aldehyde dehydrogenase. We describe here the valuable model to study molecular link between resistance to chemotherapy and metastatic dissemination.
Literature
1.
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.CrossRefPubMed
2.
Kozovska Z, Gabrisova V, Kucerova L. Colon cancer: cancer stem cells markers, drug resistance and treatment. Biomed Pharmacother. 2014;68(8):911–6.CrossRefPubMed
3.
Bose D, Zimmerman LJ, Pierobon M, Petricoin E, Tozzi F, Parikh A, Fan F, Dallas N, Xia L, Gaur P, et al. Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells. Brit J Cancer. 2011;105(11):1759–67.CrossRefPubMed
4.
Romano G, Santi L, Bianco MR, Giuffre MR, Pettinato M, Bugarin C, Garanzini C, Savarese L, Leoni S, Cerrito MG, et al. The TGF-beta pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells. Oncotarget. 2016;7:22077–91.PubMedPubMedCentral
5.
Huang WS, Hsieh MC, Huang CY, Kuo YH, Tung SY, Shen CH, Hsieh YY, Teng CC, Lee KF, Chen TC, et al. The association of CXC receptor 4 mediated signaling pathway with Oxaliplatin-resistant human colorectal Cancer cells. PLoS One. 2016;11(9):e0159927.CrossRefPubMedPubMedCentral
6.
Yang M, Liu P, Huang P. Cancer stem cells, metabolism, and therapeutic significance. Tumour Biol. 2016;37(5):5735–42.CrossRefPubMed
7.
Vidal SJ, Rodriguez-Bravo V, Galsky M, Cordon-Cardo C, Domingo-Domenech J. Targeting cancer stem cells to suppress acquired chemotherapy resistance. Oncogene. 2014;33(36):4451–63.CrossRefPubMed
8.
Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Bioly. 2013;15(4):338–44.CrossRef
9.
Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34(6):732–40.CrossRefPubMedPubMedCentral
10.
Agliano A, Calvo A, Box C. The challenge of targeting cancer stem cells to halt metastasis. Semin Cancer Biol. 2017;44:25–42.CrossRefPubMed
11.
Kemper K, Grandela C, Medema JP. Molecular identification and targeting of colorectal cancer stem cells. Oncotarget. 2010;1(6):387–95.PubMedPubMedCentral
12.
Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14(3):342–56.CrossRefPubMed
13.
Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK, Ng L, Cheung LW, Lan XR, Lan HY, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6(6):603–15.CrossRefPubMed
14.
Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468–76.CrossRefPubMed
15.
16.
Chen J, Xia Q, Jiang B, Chang W, Yuan W, Ma Z, Liu Z, Shu X. Prognostic value of Cancer stem cell marker ALDH1 expression in colorectal Cancer: a systematic review and meta-analysis. PLoS One. 2015;10(12):e0145164.CrossRefPubMedPubMedCentral
17.
Duan JJ, Cai J, Guo YF, Bian XW, Yu SC. ALDH1A3, a metabolic target for cancer diagnosis and therapy. Int J Cancer. 2016;139(5):965–75.CrossRefPubMed
18.
Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells. 2011;29(1):32–45.CrossRefPubMed
19.
Qiu Y, Pu T, Li L, Cheng F, Lu C, Sun L, Teng X, Ye F, Bu H. The expression of aldehyde dehydrogenase family in breast cancer. J Breast Canc. 2014;17(1):54–60.CrossRef
20.
Zhang W, Liu Y, Hu H, Huang H, Bao Z, Yang P, Wang Y, You G, Yan W, Jiang T, et al. ALDH1A3: a marker of mesenchymal phenotype in gliomas associated with cell invasion. PLoS One. 2015;10(11):e0142856.CrossRefPubMedPubMedCentral
21.
Cheng P, Wang J, Waghmare I, Sartini S, Coviello V, Zhang Z, Kim SH, Mohyeldin A, Pavlyukov MS, Minata M, et al. FOXD1-ALDH1A3 signaling is a determinant for the self-renewal and Tumorigenicity of mesenchymal glioma stem cells. Cancer Res. 2016;76(24):7219–30.CrossRefPubMedPubMedCentral
22.
Flahaut M, Jauquier N, Chevalier N, Nardou K, Balmas Bourloud K, Joseph JM, Barras D, Widmann C, Gross N, Renella R, et al. Aldehyde dehydrogenase activity plays a key role in the aggressive phenotype of neuroblastoma. BMC Cancer. 2016;16(1):781.CrossRefPubMedPubMedCentral
23.
Ertem FU, Zhang W, Chang K, Mohaiza Dashwood W, Rajendran P, Sun D, Abudayyeh A, Vilar E, Abdelrahim M, Dashwood RH. Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam. Int J Cancer. 2017;140(2):460–8.CrossRefPubMed
24.
Matuskova M, Baranovicova L, Kozovska Z, Durinikova E, Pastorakova A, Hunakova L, Waczulikova I, Nencka R, Kucerova L. Intrinsic properties of tumour cells have a key impact on the bystander effect mediated by genetically engineered mesenchymal stromal cells. J Gene Med. 2012;14(12):776–87.CrossRefPubMed
25.
Dallas NA, Xia L, Fan F, Gray MJ, Gaur P, van Buren G 2nd, Samuel S, Kim MP, Lim SJ, Ellis LM. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009;69(5):1951–7.CrossRefPubMedPubMedCentral
26.
Kucerova L, Skolekova S, Demkova L, Bohovic R, Matuskova M. Long-term efficiency of mesenchymal stromal cell-mediated CD-MSC/5FC therapy in human melanoma xenograft model. Gene Ther. 2014;21(10):874–87.CrossRefPubMed
27.
Matuskova M, Kozovska Z, Toro L, Durinikova E, Tyciakova S, Cierna Z, Bohovic R, Kucerova L. Combined enzyme/prodrug treatment by genetically engineered AT-MSC exerts synergy and inhibits growth of MDA-MB-231 induced lung metastases. J Exp Clin Cancer Res. 2015;34:33.CrossRefPubMedPubMedCentral
28.
Mu Y, Zang G, Engstrom U, Busch C, Landstrom M. TGFbeta-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells. Brit J Cancer. 2015;112(7):1223–31.CrossRefPubMed
29.
Xu P, Zhao M, Liu Z, Liu Y, Chen Y, Luo R, Fang W. Elevated nuclear CCND1 expression confers an unfavorable prognosis for early stage lung adenocarcinoma patients. Int J Clin Exp Pathol. 2015;8(12):15887–94.PubMedPubMedCentral
30.
McCarroll JA, Gan PP, Erlich RB, Liu M, Dwarte T, Sagnella SS, Akerfeldt MC, Yang L, Parker AL, Chang MH, et al. TUBB3/betaIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Res. 2015;75(2):415–25.CrossRefPubMed
31.
Mo X, Cao Q, Liang H, Liu J, Li H, Liu F. MicroRNA-610 suppresses the proliferation of human glioblastoma cells by repressing CCND2 and AKT3. Mol Med Rep. 2016;13(3):1961–6.CrossRefPubMedPubMedCentral
32.
Kanwar SS, Yu Y, Nautiyal J, Patel BB, Majumdar AP. The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer. 2010;9:212.CrossRefPubMedPubMedCentral
33.
Zhao JH, Luo Y, Jiang YG, He DL, Wu CT. Knockdown of beta-catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1alpha. Cancer Investig. 2011;29(6):377–82.CrossRef
34.
Redmer T, Welte Y, Behrens D, Fichtner I, Przybilla D, Wruck W, Yaspo ML, Lehrach H, Schafer R, Regenbrecht CR. The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells. PLoS One. 2014;9(5):e92596.CrossRefPubMedPubMedCentral
35.
Grunt TW, Hebar A, Laffer S, Wagner R, Peter B, Herrmann H, Graf A, Bilban M, Posch M, Hoermann G, et al. Prominin-1 (CD133, AC133) and dipeptidyl-peptidase IV (CD26) are indicators of infinitive growth in colon cancer cells. Am J Cancer Res. 2015;5(2):560–74.PubMedPubMedCentral
36.
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104(24):10158–63.CrossRefPubMedPubMedCentral
37.
O'Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106–10.CrossRefPubMed
38.
Lee MR, Ji SY, Mia-Jan K, Cho MY. Chemoresistance of CD133(+) colon cancer may be related with increased survivin expression. Biochem Bioph Res Co. 2015;463(3):229–34.CrossRef
39.
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Sem Cell. 2007;1(3):313–23.CrossRef
40.
Weichert W, Knosel T, Bellach J, Dietel M, Kristiansen G. ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. J Clin Pathol. 2004;57(11):1160–4.CrossRefPubMedPubMedCentral
41.
Manhas J, Bhattacharya A, Agrawal SK, Gupta B, Das P, Deo SV, Pal S, Sen S. Characterization of cancer stem cells from different grades of human colorectal cancer. Tumour Biol. 2016;37(10):14069–81.CrossRefPubMed
42.
Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 2007;67(13):6304–13.CrossRefPubMed
43.
Yiming L, Yunshan G, Bo M, Yu Z, Tao W, Gengfang L, Dexian F, Shiqian C, Jianli J, Juan T, et al. CD133 overexpression correlates with clinicopathological features of gastric cancer patients and its impact on survival: a systematic review and meta-analysis. Oncotarget. 2015;6(39):42019–27.CrossRefPubMedPubMedCentral
44.
Amara S, Chaar I, Khiari M, Ounissi D, Weslati M, Boughriba R, Hmida AB, Bouraoui S. Stromal cell derived factor-1 and CXCR4 expression in colorectal cancer promote liver metastasis. Cancer Biomark. 2015;15(6):869–79.CrossRefPubMed
45.
Gunaratne A, Thai BL, Di Guglielmo GM. Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor beta-induced epithelial-to-mesenchymal transition. Mol Cell Biol. 2013;33(5):874–86.CrossRefPubMedPubMedCentral
46.
Jiao J, Zhao X, Liang Y, Tang D, Pan C. FGF1-FGFR1 axis promotes tongue squamous cell carcinoma (TSCC) metastasis through epithelial-mesenchymal transition (EMT). Biochem Biophys Res Commun. 2015;466(3):327–32.CrossRefPubMed
47.
de Aguiar RB, Parise CB, Souza CR, Braggion C, Quintilio W, Moro AM, Navarro Marques FL, Buchpiguel CA, Chammas R, de Moraes JZ. Blocking FGF2 with a new specific monoclonal antibody impairs angiogenesis and experimental metastatic melanoma, suggesting a potential role in adjuvant settings. Cancer Lett. 2016;371(2):151–60.CrossRefPubMed
48.
Sun W, Gui L, Zuo X, Zhang L, Zhou D, Duan X, Ren W, Xu G. Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-β signaling pathway. J Transl Med. 2016;14(1):75.CrossRefPubMedPubMedCentral
49.
Wang HB, Yao H, Li CS, Liang LX, Zhang Y, Chen YX, Fang JY, Xu J. Rise of PD-L1 expression during metastasis of colorectal cancer: implications for immunotherapy. J Dig Dis. 2017;18(10):574–81.CrossRefPubMed
50.
Chen MH, Weng JJ, Cheng CT, Wu RC, Huang SC, Wu CE, Chung YH, Liu CY, Chang MH, Chiang KC, et al. ALDH1A3, the major aldehyde dehydrogenase isoform in human cholangiocarcinoma cells, affects prognosis and gemcitabine resistance in cholangiocarcinoma patients. Clin Cancer Res. 2016;22(16):4225–35.CrossRefPubMed
Metadata
Title
ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells
Authors
Erika Durinikova
Zuzana Kozovska
Martina Poturnajova
Jana Plava
Zuzana Cierna
Andrea Babelova
Roman Bohovic
Silvia Schmidtova
Miroslav Tomas
Lucia Kucerova
Miroslava Matuskova
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4758-y

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