levoleucovorin and Carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. TGF-β is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-β signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-β signalling synergizes with nal-IRI/5-FU/LV, a chemotherapy regimen for malignant pancreatic cancer, in an orthotopic pancreatic tumour mouse model. Compared to nal-IRI/5-FU/LV treatment, combining nal-IRI/5-FU/LV with vactosertib, a TGF-β signalling inhibitor, significantly improved long-term survival rates and effectively suppressed invasion to surrounding tissues. Through RNA-sequencing analysis, we identified that the combination treatment results in robust abrogation of tumour-promoting gene signatures and positive enrichment of tumour-suppressing and apoptotic gene signatures. Particularly, the expression of tumour-suppressing gene Ccdc80 was induced by vactosertib and further induced by vactosertib in combination with nal-IRI/5-FU/LV. Ectopic expression of CCDC80 suppressed migration and colony formation concomitant with decreased expression of epithelial-to-mesenchymal transition (EMT) markers in pancreatic cancer cells. Collectively, these results indicate that combination treatment of vactosertib with nal-IRI/5-FU/LV improves overall survival rates in a mouse model of pancreatic cancer by suppressing invasion through CCDC80. Therefore, combination therapy of nal-IRI/5-FU/LV with vactosertib could provide clinical benefits to pancreatic cancer patients.

Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Drug Synergism; Epithelial-Mesenchymal Transition; Fluorouracil; Gene Expression Regulation, Neoplastic; Irinotecan; Leucovorin; Liposomes; Mice, Inbred C57BL; Nanoparticles; Neoplasm Invasiveness; Pancreatic Neoplasms; Signal Transduction; Survival Analysis; Transcriptome; Transforming Growth Factor beta; Triazoles; Tumor Stem Cell Assay; Up-Regulation

Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Proliferation; Colorectal Neoplasms; Female; Fluorouracil; Heterografts; Humans; Leucovorin; Male; Mice; Mice, Inbred NOD; Mice, SCID; Oncogenes; Organoplatinum Compounds; Signal Transduction

Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial-mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Cell Differentiation; Cell Proliferation; Cetuximab; Culture Media, Serum-Free; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Hyaluronan Receptors; Intercellular Adhesion Molecule-1; Leucovorin; Mesoderm; Mice; Neoplastic Stem Cells; Organoplatinum Compounds; Phenotype; Rectal Neoplasms; Spheroids, Cellular; Xenograft Model Antitumor Assays