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Stem cell models for genetically predisposed colon cancer.

Nitin Telang1

  • 1Cancer Prevention Research Program, Palindrome Liaisons Consultants, Montvale, NJ 07645-1559, USA.

Oncology Letters
|September 16, 2020
PubMed
Summary

Natural products like all-trans retinoic acid and curcumin show promise against therapy-resistant colon cancer stem cells. These non-toxic agents may overcome drug resistance in familial adenomatous polyposis models.

Keywords:
adenomatous polyposis colidrug resistancestem cells

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Stem Cell Research

Background:

  • Colon cancer initiation and progression involve tumor suppressor and oncogenes, with APC gene mutations central to familial adenomatous polyposis (FAP) and sporadic colon cancer.
  • Current targeted therapies for colon cancer, including NSAIDs and enzyme inhibitors, face challenges like systemic toxicity, acquired resistance, and therapy-resistant cancer stem cells.
  • Natural products offer non-toxic alternatives with lower potential for drug resistance, making them promising for treating resistant colon cancers.

Purpose of the Study:

  • To investigate the potential of natural products, specifically all-trans retinoic acid (ATRA) and curcumin (CUR), as alternatives for therapy-resistant colon cancer.
  • To utilize preclinical FAP models with tumorigenic Apc [-/-] colonic epithelial cell lines, including Sulindac-resistant (SUL-R) cells, to study drug-resistant cancer stem cells.
  • To evaluate the efficacy of ATRA and CUR in inhibiting cancer stem cell properties like tumor spheroid formation and marker expression.

Main Methods:

  • Development of tumorigenic Apc [-/-] colonic epithelial cell lines from FAP models, including Apc [-/-] Sulindac resistant (SUL-R) cells exhibiting cancer stem cell markers.
  • Characterization of Apc [-/-] cells for aneuploid hyper-proliferation and expression of key genes (β-catenin, cyclin D1, c-myc, COX-2) compared to non-tumorigenic Apc [+/+] cells.
  • Treatment of SUL-R stem cells with ATRA and CUR to assess effects on tumor spheroid formation and expression of stem cell markers (CD44, CD133, c-Myc).

Main Results:

  • Apc [-/-] cells showed aneuploid hyper-proliferation and upregulated expression of APC target genes compared to Apc [+/+] cells.
  • SUL-R cells exhibited enhanced tumor spheroid formation and increased expression of stem cell markers (CD44, CD133, c-Myc).
  • Treatment with ATRA and CUR significantly inhibited tumor spheroid formation and reduced stem cell marker expression in SUL-R cells.

Conclusions:

  • Apc [-/-] derived stem cell models effectively represent therapy-resistant colon cancer relevant to FAP syndrome.
  • Natural products ATRA and CUR demonstrate significant anti-cancer stem cell activity in preclinical models.
  • These findings highlight the potential of natural products as viable, non-toxic alternatives for treating therapy-resistant, genetically predisposed colon cancer.