Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

Scartozzi, Mario; Bearzi, Italo; Berardi, Rossana; Mandolesi, Alessandra; Pierantoni, Chiara; Cascinu, Stefano

doi:10.1038/sj.bjc.6603847

Cited by 39 publications

(28 citation statements)

References 16 publications

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“…The downregulation in metastases has recently been indicated also in other previously published studies (32)(33)(34). EGFR overexpression has been found to be associated with tumor progression and poor survival in several tumor types, such as in CRC (35), and importantly, our results underlined the involvement of NHERF1 along with EGFR in the CRC progression.…”

Section: Discussionsupporting

confidence: 87%

Involvement of nuclear NHERF1 in colorectal cancer progression

Mangia¹,

Saponaro²,

Malfettone³

et al. 2012

Oncology Reports

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Abstract. NHERF1 (Na + /H + exchanger regulatory factor 1) is expressed in the luminal membrane of many epithelia, and associated with proteins involved in tumor progression. Alterations of NHERF1 expression in different sites of metastatic colorectal cancer (mCRC) suggest a dynamic role of this protein in colon carcinogenesis. We focused on the observation of the altered expression of NHERF1 from non-neoplastic tissues to metastatic sites by immunohistochemistry. Moreover, we studied, by immunofluorescence, the colocalization between NHERF1 and the epidermal growth factor receptor (EGFR), whose overexpression is implicated in CRC progression. NHERF1 showed a different localization and expression in the examined sites. The distant non-neoplastic tissues showed NHERF1 mostly expressed at the apical membrane, while in surrounding non-neoplastic tissue decreased the apical membrane and increased cytoplasmic immunoreactivity. In adenomas a shift from apical membrane to cytoplasmic localization and nuclear expression were observed. Cytoplasmic staining in the tumor, and metastatic sites was stronger than surrounding non-neoplastic tissue. Furthermore, nuclear NHERF1 expression was noted in 80% of all samples and surprisingly, it appeared already in adenoma lesions, suggesting that NHERF1 represents an early marker of pre-morphological triggering of colorectal carcinogenesis. Then, in few tumors a positive direct correlation between membrane NHERF1 and EGFR expression was evidenced by their colocalization. Nuclear NHERF1 expression, present in the early stages of carcinogenesis and related with poor prognosis, may contribute to the onset of malignant phenotype. Specifically, we hypothesize the direct involvement of nuclear NHERF1 in both carcinogenesis and progression and its role as a potential colorectal cancer marker. IntroductionColorectal cancer (CRC) is the second most common cause of cancer related death in the Western societies (1). At the time of diagnosis 19% of patients will present synchronous metastasis and 30-40% of patients will develop distant metachronous metastasis (2). The liver is one of the most common sites of metastasis and many molecular variables are still unclear. Some studies have suggested that the accumulation of specific alterations in cell growth genes are involved in cancer progression (3) and tumorigenesis (4). Thus, different gene expression can lead to unique transcriptional outcomes and consequently a multiple signalling pathways can be simultaneously activated. NHERF1 (Na + /H + exchanger regulatory factor 1, also named EBP50) is an adaptor protein that links several cellular receptors, ion transporters and other proteins to the plasma membrane of different types of cells (5-9). The association between specific growth factor receptors and NHERF1 has already been analysed (8-10) and indicates a critical role for this adaptor protein in growth factor signal transduction. Recently in normal cells, the level of NHERF1 expression has been demonstrated to have effects on the trafficking,...

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Section: Discussionsupporting

confidence: 87%

Involvement of nuclear NHERF1 in colorectal cancer progression

Mangia¹,

Saponaro²,

Malfettone³

et al. 2012

Oncology Reports

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“…However, our results indicate lower EGFR positivity in the metastases. Downregulation in metastases have recently been indicated also in other studies (20,(33)(34)(35).…”

Section: ------------------------------------------------------------supporting

confidence: 53%

“…The fraction of tumor cells being EGFR-positive varied in the range 20-95% (12,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). The variations in expression of EGFR in lymph node (28,30,33) and liver metastases (29)(30)(31)(32)(33)(34)(35) were similarly high. Our values for the Hangzhou patients are in the lower part of the ranges.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy

Wei

Shui²,

Zheng³

et al. 2010

Oncol Rep

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Abstract. Members of the epidermal growth factor receptor, EGFR, family are interesting as targets for radionuclide therapy using targeting agents labeled with ·-or ß-emitting radionuclides, especially when EGFR-positive colorectal carcinomas, CRC, are resistant to EGFR inhibiting agents like cetuximab and various tyrosine kinase inhibitors. The expression of EGFR, HER2 and HER3 was therefore analyzed in CRC samples from primary tumors, corresponding lymph node metastases and, in a few cases, liver metastases. The expression of HER2 and EGFR was scored from immunohistochemical preparations using the HercepTest criteria 0, 1+, 2+ or 3+ for cellular membrane staining while HER3 expression was scored as no, weak or strong cytoplasm staining. Material from 60 patients was analyzed. The number of EGFR 2+ or 3+ positive primary tumors was 16 out of 56 (29%) and for lymph node metastases 8 out of 56 (14%) whereas only one out of nine (11%) liver metastases were positive. Thus, there was lower EGFR positivity in the metastases. Only one among 53 patients was strongly HER2 positive and this in both the primary tumor and the metastasis. Eight out of 49 primary tumors (16%) were strongly HER3 positive and the corresponding numbers for lymph node metastases were 9 out of 49 (18%) and for liver metastases 2 out of 9 (22%). The observed number of strongly EGFR positive cases was somewhat low but EGFR might be, for the cases with high EGFR expression in metastases, a target for radionuclide therapy. HER2 seems not to be of such interest due to rare expression, neither HER3 due to mainly expression in the cytoplasm. The requirements for successful EGFR targeted radionuclide therapy are discussed, as well as patient inclusion criteria related to radionuclide therapy.

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“…Recent studies, evaluating the clinical response in patients with advanced or metastatic colorectal cancer, showed that the presence of KRAS mutation is associated with the lack of response to cetuximab [24,[33][34][35][36][37]. Patients without mutations in the KRAS gene gain therapeutic benefit from the use of cetuximab [38]. Similarly, the use of panitumumab in patients with the presence of KRAS mutations, did not bring the expected therapeutic benefit [24].…”

Section: Discussionmentioning

confidence: 99%

Molecular differences in the KRAS gene mutation between a primary tumor and related metastatic sites - case report and a literature review.

Kosakowska¹,

Stec²,

Charkiewicz³

et al. 2011

Folia Histochem Cytobiol.

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Abstract:In recent years the the set of diagnostic tools in colorectal cancers has been extended by the assessment of the KRAS gene status. Currently it is a necessary step in order to qualify patients for the targeted therapy. The results of the analysis of several studies revealed a high rate of compliance of the KRAS gene mutational status in primary and metastatic tumors. In this paper we present a rare case of incompatibility of the KRAS mutations in the primary tumor located in the colon and metastatic changes in the liver.

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Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

Cited by 39 publications

References 16 publications

Involvement of nuclear NHERF1 in colorectal cancer progression

Involvement of nuclear NHERF1 in colorectal cancer progression

EGFR, HER2 and HER3 expression in primary colorectal carcinomas and corresponding metastases: Implications for targeted radionuclide therapy

Molecular differences in the KRAS gene mutation between a primary tumor and related metastatic sites - case report and a literature review.

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