Gastroenterology

Gastroenterology

Volume 141, Issue 3, September 2011, Pages 1046-1056
Gastroenterology

Original Research
Basic and Translational-Alimentary Tract
Mesenchymal Stem Cells Promote Formation of Colorectal Tumors in Mice

https://doi.org/10.1053/j.gastro.2011.05.045Get rights and content

Background & Aims

Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation.

Methods

Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation.

Results

A small number (≤10) of unsorted, CD133, CD166, epithelial cell adhesion molecule(EpCAM), or CD133/CD166/EpCAM colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2–signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation.

Conclusions

IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer.

Section snippets

Primary Cells and Cell Lines

The human colorectal cancer cell line HT-29 was obtained from the American Type Culture Collection and grown in Dulbecco's modified Eagle medium (Gibco, Grand Island, NY) containing 100 U/mL penicillin, 100 μg/mL streptomycin, 4 mmol/L glutamine, and 10% fetal bovine serum (Gibco). The MSC cell line was immortalized by retroviral transduction of HPV16 E6E7 and grown in Dulbecco's modified Eagle medium–low glucose (Gibco) supplemented with 10% fetal bovine serum.8 Primary MSCs from different

Nontransformed Cells Derived From Various Tissues Promote Colorectal Tumor Initiation and Tumor Sphere Formation

To investigate the functional consequences of the heterotypic interactions between HT-29 colorectal cancer cells (CCCs) and nontransformed cells (NTCs) derived from various tissues, the growth kinetics of the nontransformed cells containing tumors (CCCs plus NTCs) was compared with those of CCCs or NTCs alone in a xenograft model of immunocompromised mice. We found that co-injection with MSCs, WI38 lung fibroblasts, primary DFs, or primary GE, but not with 293 adenoviral-transfected human

Discussion

Recently, tumors formed by an unsorted single tumor cell after transplantation into a highly immunocompromised mouse (with IL-2–receptor-γ chain deletion in nonobese diabetic/severe combined immunodeficient mice) was achieved in melanoma.23 The current study also showed a single unsorted or CD133-CD166-EpCAM triple-negative colorectal cancer cell admixed with MSCs, up to 5%–7% of the injections formed tumors in mice. It is yet to be determined whether the MSC-enhanced TICs in colon cancer also

Acknowledgments

S.-H.Y. and Y.-P.L. contributed equally to this article.

References (28)

  • A.E. Karnoub et al.

    Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

    Nature

    (2007)
  • M.B. Meads et al.

    Environment-mediated drug resistance: a major contributor to minimal residual disease

    Nat Rev Cancer

    (2009)
  • S.C. Hung et al.

    Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging

    Clin Cancer Res

    (2005)
  • I. Sekiya et al.

    Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality

    Stem Cells

    (2002)
  • Cited by (0)

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the National Science Council (3111-B-039, 96-2627-B-010-009, 97-3111-B-010-001, and 99-3111-B-010-005-), Taipei Veterans General Hospital (V97C1-060, V98C1-009, and V98E1-002), the MD Anderson Cancer Center/China Medical University and Hospital Sister Institution Fund, and the National Yang-Ming University, Ministry of Education. This work was assisted in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital.

    View full text