ERBB3 Positively Correlates with Intestinal Stem Cell Markers but Marks a Distinct Non Proliferative Cell Population in Colorectal Cancer

PLoS One. 2015 Sep 14;10(9):e0138336. doi: 10.1371/journal.pone.0138336. eCollection 2015.

Abstract

Several studies have suggested ERBB3/HER3 may be a useful prognostic marker for colorectal cancer. Tumours with an intestinal stem cell signature have also been shown to be more aggressive. Here, we investigate whether ERBB3 is associated with intestinal stem cell markers in colorectal cancer and if cancer stem cells within tumours are marked by expression of ERBB3. Expression of ERBB3 and intestinal stem cell markers (LGR5, EPHB2, CD44s and CD44v6) was assessed by qRT-PCR in primary colorectal tumours (stages 0 to IV) and matched normal tissues from 53 patients. The localisation of ERBB3, EPHB2 and KI-67 within tumours was investigated using co-immunofluorescence. Expression of ERBB3 and intestinal stem cell markers were significantly elevated in adenomas and colorectal tumours compared to normal tissue. Positive correlations were found between ERBB3 and intestinal stem cell markers. However, co-immunofluorescence analysis showed that ERBB3 and EPHB2 marked specific cell populations that were mutually exclusive within tumours with distinct proliferative potentials, the majority of ERBB3+ve cells being non-proliferative. This pattern resembles cellular organisation within normal colonic epithelium where EPHB2 labelled proliferative cells reside at the crypt base and ERBB3+ve cells mark differentiated cells at the top of crypts. Our results show that ERBB3 and intestinal stem cell markers correlate in colorectal cancers. ERBB3 localises to differentiated cell populations within tumours that are non-proliferative and distinct from cancer stem cells. These data support the concept that tumours contain discrete stem, proliferative and differentiation compartments similar to that present in normal crypts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Antigens, Differentiation / biosynthesis*
  • Antigens, Differentiation / genetics
  • Cell Line, Tumor
  • Cell Proliferation*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Receptor, ErbB-3 / biosynthesis*
  • Receptor, ErbB-3 / genetics

Substances

  • Antigens, Differentiation
  • ERBB3 protein, human
  • Receptor, ErbB-3

Grants and funding

The authors acknowledge support for this work from the National Health and Medical Research Council (Australia) project grants 1010429 to HA and PJM, and 1011187 to HA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.