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. 2017 Dec 19;12(12):e0189953.
doi: 10.1371/journal.pone.0189953. eCollection 2017.

Consistent Expression of Guanylyl cyclase-C in Primary and Metastatic Gastrointestinal Cancers

Free PMC article

Consistent Expression of Guanylyl cyclase-C in Primary and Metastatic Gastrointestinal Cancers

Hadi Danaee et al. PLoS One. .
Free PMC article


Background: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues.

Methods: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors. Tissue specimens consisted of tissue microarrays containing esophageal, gastric, pancreatic tumors, and whole-slide tissue sections from colorectal cancer patients with matching primary and metastatic tumors.

Result: Among the evaluated esophageal, gastric, and pancreatic tumors, the frequency of GCC positivity at the protein level ranged from 59% to 68%. GCC was consistently expressed in primary and matched/synchronous metastatic lesions of colorectal cancer tissues derived from the same patients.

Conclusion: This observational study demonstrated the protein expression of GCC across various gastrointestinal malignancies. In all cancer histotypes, GCC protein localization was observed predominantly in the cytoplasm compared to the membrane region of tumor cells. Consistent immunohistochemistry detection of GCC protein expression in primary colorectal cancers and in their matched liver metastases suggests that the expression of GCC is maintained throughout the process of tumor progression and formation of metastatic disease.

Conflict of interest statement

Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: HD, TK, and WLT are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, at the time this work was conducted. TW and FG were employees of Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, at the time this work was conducted. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors have declared that no competing interests exist.


Fig 1
Fig 1. Representative GCC protein expression in GI tumors.
(A and B) high and low cytoplasmic expression of GCC in two cases of esophageal squamous cell carcinoma, respectively; (C) strong membranous-apical staining of a pancreatic ductal adenocarcinoma; and (D) weak cytoplasmic staining of a pancreatic adenocarcinoma. All sections are magnified by a factor of 20x. GCC, guanylyl cyclase-C; GI, gastrointestinal.
Fig 2
Fig 2. Representative GCC expression in matched primary and metastatic gastric adenocarcinomas.
(A and C) two primary gastric intestinal-type adenocarcinomas showing strong membranous-apical staining combined with weak cytoplasmic GCC expression, respectively; (B and D) matching lymph-node metastases from two primary cases showing consistent GCC expression with both membranous-apical and cytoplasmic localization. All sections are magnified by a factor of 20x. GCC, guanylyl cyclase-C.
Fig 3
Fig 3. Representative GCC expression in primary CRC and matched liver metastases.
(A and C) Strong apical-membrane GCC staining is seen in primary colorectal adenocarcinomas; (B and D) the observed membrane-apical staining is also consistent with observations in the matched liver metastasis. All sections are magnified by a factor of 20x. CRC, colorectal cancers; GCC, guanylyl cyclase-C.

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Grant support

This study was funded by Takeda Pharmaceuticals International Co (URL: Moreover, Takeda Pharmaceuticals provided support in the form of salaries for authors (HD, TK, TW, FG, and WLT) but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.