Gene Expression Signatures of a Preclinical Mouse Model during Colorectal Cancer Progression under Low-Dose Metronomic Chemotherapy

Abstract

Understanding the molecular signatures of colorectal cancer progression under chemotherapeutic treatment will be crucial for the success of future therapy improvements. Here, we used a xenograft-based mouse model to investigate, how whole transcriptome signatures change during metastatic colorectal cancer progression and how such signatures are affected by LDM chemotherapy using RNA sequencing. We characterized mRNAs as well as non-coding RNAs such as microRNAs, long non-coding RNAs and circular RNAs in colorectal-cancer bearing mice with or without LDM chemotherapy. Furthermore, we found that circZNF609 functions as oncogene, since over-expression studies lead to an increased tumor growth while specific knock down results in smaller tumors. Our data represent novel insights into the relevance of non-coding and circRNAs in colorectal cancer and provide a comprehensive resource of gene expression changes in primary tumors and metastases. In addition, we present candidate genes that could be important modulators for successful LDM chemotherapy.

Longitudinal examination of perfusion and angiogenesis markers in primary colorectal tumors shows distinct signatures for metronomic and maximum-tolerated dose strategies

“…A critical component that needs to be addressed before MET NAC can be studied at the clinical level in CRC pertains its effect on the angiogenic program of tumors. Because tumor response is a microenvironment-dependent process, there is a need to examine if MET is able to cause the same anti-angiogenic effect in primary tumors that has been previously reported in subcutaneous models of this disease 51 , [52] .…”

Addressing Genetic Tumor Heterogeneity, Post-Therapy Metastatic Spread, Cancer Repopulation, and Development of Acquired Tumor Cell Resistance

“…Metronomic, very low-dose chemotherapy promotes a continuous pattern of stress responses [ 55 , 123 , 124 , 125 ]. The present clinical data reveal that metronomic chemotherapy at ‘very’ low-doses limits tumor tissue plasticity by stress response, probably decreasing phenotypic heterogeneity of tumor cell niches as tissue stress generally induces a tighter phenotype [ 123 , 126 , 127 , 128 , 129 , 130 , 131 ]. Thus, metronomic chemotherapy might induce phenotypic integration of inflammation control or differentiation by editing techniques and, consecutively, may serve as an enhancer of pro-anakoinotic effects mediated by added transcriptional modulators [ 55 , 123 ].…”