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Transforming growth factor-beta pathway disruption and infiltration of colorectal cancers by intraepithelial

K Baker1, G Chong, W D Foulkes

  • 1Department of Pathology, SMBD-Jewish General Hospital, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada. kristi.baker@mcgill.ca

Histopathology
|September 19, 2006
PubMed
Abstract

Insights

Colorectal cancers with DNA mismatch repair deficiency retain lymphocytes due to transforming growth factor-beta (TGF-beta) pathway insensitivity. This TGF-beta refractoriness, linked to better prognosis, suggests targeting this pathway for cancer therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Colorectal cancers deficient in DNA mismatch repair (MMR) often exhibit numerous intraepithelial lymphocytes (IELs).
  • These CD8+ T cells express CD103, upregulated by transforming growth factor-beta (TGF-beta), and bind to E-cadherin on mucosal epithelia.
  • Many MMR-deficient cancers have mutations in the TGF-beta type II receptor, suggesting TGF-beta insensitivity.

Purpose of the Study:

  • To investigate if refractoriness to TGF-beta signaling contributes to IEL retention in colorectal cancers.
  • To identify predictors of increased lymphocytic infiltration independent of MMR status.

Main Methods:

  • Immunohistochemistry was used to analyze TGF-beta pathway components in MMR-deficient colorectal cancers.
  • Logistic regression analysis identified predictors of elevated lymphocytic infiltration.

Main Results:

  • Increased Smad4 expression was an independent predictor of marked lymphocyte infiltration.
  • Tumor cell proliferation and TGF-beta secretion also independently predicted higher lymphocyte infiltration.
  • These factors were identified independently of DNA mismatch repair status.

Conclusions:

  • Refractoriness to TGF-beta signaling in colorectal cancers plays a role in retaining lymphocytes within the tumor epithelium.
  • IEL infiltration is an independent predictor of a favorable prognosis.
  • The TGF-beta pathway represents a potential therapeutic target for colorectal cancer.

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