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Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature.

ABSTRACT: Acquired resistance to anti-angiogenic tyrosine kinase inhibitors is an important clinical problem in treating various cancers. To what extent acquired resistance is determined by microenvironmental host-factors or by tumor cells directly is unknown. We previously found that tumor cells can become resistant to sunitinib in vitro. Here, we studied to what extent in vitro induced resistance of tumor cells determines in vivo resistance to sunitinib. In severe combined immunodeficient mice, tumors were established from HT-29 parental colon cancer cells (HT-29PAR) or the in vitro induced sunitinib resistant HT-29 cells (HT-29SUN). Treatment with sunitinib (40mg/kg/day) inhibited tumor growth of HT-29PAR tumors by 71±5%, while no inhibition of HT-29SUN tumor growth was observed. Intratumoral sunitinib concentrations and reduced MVD were similar in both groups. Ki67 staining revealed that tumor cell proliferation was significantly reduced with 30% in HT-29PAR tumors, but unaffected in HT-29SUN tumors upon sunitinib treatment. The lysosomal capacity reflected by LAMP-1 and -2 expression was higher in HT-29SUN compared to HT-29PAR tumors indicating an increased sequestration of sunitinib in lysosomes of resistant tumors. In conclusion, we demonstrate that tumor cells rather than host-factors may play a crucial role in acquired resistance to sunitinib in vivo.

SUBMITTER: Gotink KJ

PROVIDER: S-EPMC4303892 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature.

Gotink Kristy J KJ Broxterman Henk J HJ Honeywell Richard J RJ Dekker Henk H de Haas Richard R RR Miles Kiersten M KM Adelaiye Remi R Griffioen Arjan W AW Peters Godefridus J GJ Pili Roberto R Verheul Henk M W HM

Oncoscience 20141215 12

Acquired resistance to anti-angiogenic tyrosine kinase inhibitors is an important clinical problem in treating various cancers. To what extent acquired resistance is determined by microenvironmental host-factors or by tumor cells directly is unknown. We previously found that tumor cells can become resistant to sunitinib in vitro. Here, we studied to what extent in vitro induced resistance of tumor cells determines in vivo resistance to sunitinib. In severe combined immunodeficient mice, tumors w ...[more]

PMID: 25621299

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Project description:BackgroundEpithelial cells in malignant conditions release DNA into the extracellular compartment. Cell free DNA of tumor origin may act as a ligand of DNA sensing mechanisms and mediate changes in epithelial-stromal interactions.AimsTo evaluate and compare the potential autocrine and paracrine regulatory effect of normal and malignant epithelial cell-related DNA on TLR9 and STING mediated pathways in HT-29 human colorectal adenocarcinoma cells and normal fibroblasts.Materials and methodsDNA isolated from normal and tumorous colonic epithelia of fresh frozen surgically removed tissue samples was used for 24 and 6 hour treatment of HT-29 colon carcinoma and HDF-? fibroblast cells. Whole genome mRNA expression analysis and qRT-PCR was performed for the elements/members of TLR9 signaling pathway. Immunocytochemistry was performed for epithelial markers (i.e. CK20 and E-cadherin), DNA methyltransferase 3a (DNMT3a) and NF?B (for treated HDF? cells).ResultsAdministration of tumor derived DNA on HT29 cells resulted in significant (p<0.05) mRNA level alteration in 118 genes (logFc?1, p?0.05), including overexpression of metallothionein genes (i.e. MT1H, MT1X, MT1P2, MT2A), metastasis-associated genes (i.e. TACSTD2, MACC1, MALAT1), tumor biomarker (CEACAM5), metabolic genes (i.e. INSIG1, LIPG), messenger molecule genes (i.e. DAPP, CREB3L2). Increased protein levels of CK20, E-cadherin, and DNMT3a was observed after tumor DNA treatment in HT-29 cells. Healthy DNA treatment affected mRNA expression of 613 genes (logFc?1, p?0.05), including increased expression of key adaptor molecules of TLR9 pathway (e.g. MYD88, IRAK2, NF?B, IL8, IL-1?), STING pathway (ADAR, IRF7, CXCL10, CASP1) and the FGF2 gene.ConclusionsDNA from tumorous colon epithelium, but not from the normal epithelial cells acts as a pro-metastatic factor to HT-29 cells through the overexpression of pro-metastatic genes through TLR9/MYD88 independent pathway. In contrast, DNA derived from healthy colonic epithelium induced TLR9 and STING signaling pathway in normal fibroblasts.

Dataset Information

Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature.

Publications

Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature.

Similar Datasets

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