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Identification of miRNAs during colorectal cancer progression and metastasis using a preclinical mouse model during LDM topotecan chemotherapy

ABSTRACT: To find candidate circRNAs and to unravel their molecular functions during colorectal cancer progression and during LDM topotecan chemotherapy, we utilized a xenograft mouse model based on the HT29.hCG.Luc colorectal cancer cell line (referred to as HT29) implanted into SCID mice. HT29 cells were injected into the spleen and primary tumors developed. Three mice served as control group while two mice served as LDM topotecan treated group. After another 4-6 weeks, liver metastasis can be detected and resected for further investigation. For a global view on miRNA changes, we performed miRNA-Seq from HT29 cells, primary tumors and liver metastases from control mice (C-PT and C-LM) and liver metastases from treated mice (T-LM).

ORGANISM(S): Homo sapiens

PROVIDER: GSE163074 | GEO | 2021/01/13

REPOSITORIES: GEO

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Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).

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Identification of miRNAs during colorectal cancer progression and metastasis using a preclinical mouse model during LDM topotecan chemotherapy

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