Abstract
Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61) decreases the cell viability of organoids compared with Notch (YO-01027, DAPT) and Wnt (WAV939, Wnt-C59) signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer.
Highlights
Colorectal cancer is one of the most common causes of cancer-related mortality worldwide [1,2]
The major findings of the present study are as follows: (1) Hedgehog signal inhibitors were more effective on decreasing the cell viability of tumor organoids compared with Wnt and Notch signal inhibitors (Figure 1). (2) The combination treatment with Hedgehog signal inhibitor and
5-FU, Irinotecan or Oxaliplatin effectively decreased the cell viability of tumor organoids (Figure 1). (3) In tumor organoids, expression of c-Myc, CD44 and Nanog was inhibited by Hedgehog signal inhibitors likely through the decrease of GLI-1 expression (Figure 1). (4) The combination treatment with Hedgehog inhibitor and 5-FU or Irinotecan prevented colony formation of HCT116 and SW480 (Figure 1)
Summary
Colorectal cancer is one of the most common causes of cancer-related mortality worldwide [1,2]. Patients are conventionally treated with surgery, chemotherapy and radiotherapy. About 50% of patients are diagnosed at late stage and develop liver metastasis, which leads to the low survival rate [3]. In patients with metastatic colorectal cancer, the combination treatment of 5-fluorouracil (5-FU), Folinic acid and Oxaliplatin (FOLFOX) (5-FU), Folinic acid and Irinotecan (FOLFIRI) is employed and improves overall survival in some patents. Most patients develop a drug resistance during the course of treatment [4]. Understanding the mechanisms underlying the resistance is essential for the development of effective treatments
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