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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 4  |  Page : 150-156

Activation of epidermal growth factor receptor/insulin-like growth factor 1 receptor-β-Catenin-CD44 pathway in periampullary cancer


1 Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
2 Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India

Date of Submission08-Oct-2020
Date of Acceptance05-Nov-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Chinmay Kumar Panda
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_54_20

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  Abstract 


Background: Periampullary cancer (PC) is a global medical burden. Less than 5% of patients experience an overall survival of 5 years or more. The study aims to analyze the importance of epidermal growth factor receptor (EGFR)/insulin-like growth factor 1 receptor (IGF1R)–beta-catenin (β-catenin)–CD44 pathway in the development of periampullary cancer of Indian patients. Subjects and Methods: Expression profile of EGFR, IGF1R, β-catenin, and CD44 was verified by immunohistochemical analysis in primary tumor samples (N = 14) and respective adjacent normal tissues. Results: In periampullary carcinoma patients, a high level of EGFR expression was seen in 64% of the samples along with co-expression of IGF1R in 77.8% of samples. Furthermore, the high expression of EGFR and IGF1R significantly correlated with the increased expression of β-catenin along with CD44 expression of the tumors. Conclusion: The EGFR/IGF1R–β-catenin–CD44 pathway seems to be important in the development of PC with clinical importance.

Keywords: Beta-catenin, CD44, epidermal growth factor receptor, insulin-like growth factor 1 receptor, periampullary cancer


How to cite this article:
Bankura B, Maji S, Chakraborty B, Alam N, Panda CK. Activation of epidermal growth factor receptor/insulin-like growth factor 1 receptor-β-Catenin-CD44 pathway in periampullary cancer. J Radiat Cancer Res 2020;11:150-6

How to cite this URL:
Bankura B, Maji S, Chakraborty B, Alam N, Panda CK. Activation of epidermal growth factor receptor/insulin-like growth factor 1 receptor-β-Catenin-CD44 pathway in periampullary cancer. J Radiat Cancer Res [serial online] 2020 [cited 2021 Jan 17];11:150-6. Available from: https://www.journalrcr.org/text.asp?2020/11/4/150/305726




  Introduction Top


Periampullary carcinoma (PC) is a group of adenocarcinomas that originated from the head of the pancreas, the distal bile duct, the ampulla of Vater, and the duodenum.[1] These tumors are arising either from the epithelium, connective tissue, lymphoid tissue, or the neuroendocrine cells in that anatomic region.[2] Carcinoma of the head of the pancreas is the most prevalent type of periampullary adenocarcinoma, representing 3% of all malignant growth in the USA[3] and the Nordic nations.[4] It is accountable for 7% of all cancer-related deaths, making it the Western world's fourth most common cause of cancer-associated death.[3],[4] The rate of pancreatic cancer in India is 0.5–2.4 per 100,000 men and 0.2–1.8 in keeping with 100,000 women,[5] while the occurrence of periampullary carcinoma has risen over the last three decades.[6] Due to the structural complexity with numerous kinds of epithelium merged at the originating site, the specific epithelial source of PC has been unclear. Moreover, while pancreaticoduodenectomy has been the main treatment stay for patients with localized disease, the role of systemic or targeted therapies in adjuvant or advanced, unresectable disease remains uncertain.[7] Moreover, due to the paucity of PC samples, studies on molecular alterations and molecular prognostic factors for patients with PC are limited. Thus, for early detection and proper tumor therapy intervention, molecular understanding of the disease is critical.

Growth factor receptors, such as epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R), have been appeared to play a vital role in cell proliferation, antiapoptosis, angiogenesis, and metastasis.[8],[9],[10] EGFR is responsible in the process of tumor development of several types of cancers, such as lung, breast, kidney, and prostate. It has been utilized as a molecular target for the treatment of several carcinomas such as advanced nonsmall cell carcinoma of the lung (NSCLC), metastatic pancreatic cancer, and metastatic colorectal carcinoma.[11],[12] Current studies have recommended a crosstalk between IGF1R and EGFR signaling pathways and that IGF1R might be responsible for EGFR therapy failure.[13],[14] It is shown that IGF1R is highly expressed in breast carcinoma,[15] prostatic carcinoma,[16] and NSCLC.[17]

High-level co-expression of EGFR and IGF1R is associated with poor survival in patients with NSCLC after resection.[15] β-catenin (CTNNB1), a catenin family protein, acts as a vital part of the cytoskeleton, thus regulating cell adhesion.[18],[19] It also performs a key function in gene expression, being an aspect of the Wnt signaling pathway.[18],[19] In several types of carcinoma, the stimulation of β-catenin is mediated by EGFR interaction with the core region of β-catenin and induces tyrosine phosphorylation of catenin.[20],[21] Furthermore, EGFR and IGF1R both inactivate glycogen synthase kinase 3 beta, an inhibitor of the β-catenin signaling, through phosphoinositide 3-kinase/protein kinase B (Akt) signaling pathway that results in the accumulation of β-catenin and the activation of its downstream targets, such as CD44.[22],[23] This increases the possibility that EGFR and IGF1R signaling may play a role in β-catenin regulation in PCs. To the best of our knowledge, the importance of the EGFR/IGF1R–β-catenin–CD44 pathway in the development of PC has not been studied.

Thus, in the present study, we would like to understand the importance of EGFR/IGF1R in the regulation of β-catenin–CD44 pathway in the development of PC. For this purpose, EGFR, IGF1R, β-catenin, and CD44 protein expressions were analyzed by immunohistochemistry in 14 primary PC samples of Indian patients at different clinical stages.


  Subjects and Methods Top


Patient samples

This study was approved by the institutional ethical committee of Chittaranjan National Cancer Institute (CNCI), Kolkata. Freshly operated PC samples (n = 14) and adjacent normal tissues of the respective patients were collected from the Department of Surgery, CNCI, Kolkata. All participants in this study had given written consent. Sample demographics are summarized in [Table 1]. The majority of the patients were male (58%) and the mean age of the patients was 52 ± 8.12 years. Among the samples, 14% were in TNM Stage I, 36% in Stage II, 43% in Stage III, and 7% in Stage IV [Table 1]. Tumor and normal samples were collected immediately after operation and fixed in 10% buffered formalin. The paraffin block was prepared for expression analysis according to the standard procedure.
Table 1: Patient demographic data

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Histopathological analysis

Routine histopathological analysis of all tissue samples was conducted as per the standard protocol to validate them before expression analysis.[24] H and E stain was done for all the samples and examined under a bright-field microscope (Leica Microsystems Inc.) followed by an examination by two independent pathologists for histological analysis.

Immunohistochemical analysis

The expression analysis was performed through immunohistochemical analysis according to the standard protocol.[24] The 5-μm paraffin sections of cancer and adjacent normal samples were treated by xylene for deparaffinization followed by rehydration with descending ethanol grades. The antigen retrieval was carried out with 10 mM citrate buffer (pH 6.0) at 85°C for 30 min. After that, slides were blocked with 3% H2O2 for 10 min followed by incubation with 3% blocking solution (bovine serum albumin) at room temperature for 2 h. Then, primary antibodies at a dilution of 1:80–1:100 were used for overnight incubation. The primary antibodies of EGFR (Sc-03), IGF1R (Sc-463), β-catenin (sc-7199), and CD44 (sc-7297) were purchased from Santa Cruz Biotechnology, Inc., USA. The HRP-conjugated respective secondary antibodies (Santa Cruz Biotechnology, Inc.,) at a dilution of 1:500–1:1000 were used. After incubation with secondary antibody, diaminobenzidine (Sigma, USA) was used for color substrate reaction, accompanied by nuclear stain with hematoxylin. The expression pattern was scored by two observers independently according to Perrone et al.[25] as described previously.[26]

Statistical analysis

The comparative analysis was performed in between tumor samples with their respective normal tissue. As per the requirement, t-test (for continuous variables) and Chi-square test (for categorical variables) were performed. Pearson's correlation coefficient (linear regression) test was done to find out the association between different protein expressions. P < 0.05 was considered statistically significant.


  Results and Discussion Top


Analysis the expression of EGFR, IGF1R, β-catenin and CD44 protein

In normal tissue, membrane expression of EGFR protein was evident in around 9.64% of the cells [Figure 1]a and [Figure 1]b. Compared to normal tissue, significant increase in the expression of EGFR protein was seen in Stage I + II tumor cells (27.85%, P = 0.0009) and Stage III + IV tumor cells (42.14%, P ?= 0.0003). In [Figure 1],[Figure 2],[Figure 3],[Figure 4] *indicate statistically significant. [Figure 1]a and [Figure 1]b. Similar expression pattern of EGFR has also been seen previously in pancreatobiliary-type ampullary adenocarcinomas (42%).[27]
Figure 1: Immunohistochemical expression analysis of epidermal growth factor receptor in PC. (a) Representative photographs of epidermal growth factor receptor expression in normal tissue and PC. Magnification × 20, inset magnification ×40, scale bar 50 μm. Arrows indicate positive cells. (b) Representative histogram showing the percentage of cells showing epidermal growth factor receptor expression in normal tissue and different stages of PC samples represent a significant P < 0.05 compared to normal tissue, * statistically significant.

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Figure 2: Immunohistochemical expression analysis of insulin-like growth factor 1 receptor in PC. (a) Representative photographs of insulin-like growth factor 1 receptor expression in normal tissue and PC. Magnification ×20, inset magnification ×40, scale bar 50 μm. Arrows indicate positive cells. (b) Representative histogram showing the percentage of cells showing insulin-like growth factor 1 receptor expression in normal tissue and different stages of PC samples represent a significant P < 0.05 compared to normal tissue, *statistically significant

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Figure 3: Immunohistochemical expression analysis of β-catenin in PC. (a) Representative photographs of β-catenin expression in normal tissue and PC. Magnification × 20, inset magnification × 40, scale bar 50 μm. Arrows indicate positive cells. (b) Representative histogram showing the percentage of cells showing β-catenin expression in normal tissue and different stages of PC samples represent a significant P < 0.05 compared to normal tissue *statistically significant

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Figure 4: Immunohistochemical expression analysis of CD44 in PC. (a) Representative photographs of CD44 expression in normal tissue and PC. Magnification × 20, inset magnification × 40, scale bar 50 μm. Arrows indicate positive cells. (b) Representative histogram showing the percentage of cells showing CD44 expression in normal tissue and different stages of PC samples represent a significant P < 0.05 compared to normal tissue *statistically significant

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To the best of our knowledge, very few studies have been done to reveal the expression pattern of IGF1R in the PC samples. Like EGFR, low membrane expression of the IGF1R was seen in 12.5% of the cells of normal tissue followed by significant increase in Stage I + II tumor cells (27.85%, P = 0.0009) and Stage III + IV tumor cells (45.7%, P = 0.0007) [Figure 2]a and [Figure 2]b. Similarly, IGF1R expression was seen in 41% of pancreatic ductal adenocarcinomas in an earlier report.[28]

In normal tissue, membrane and nuclear/cytoplasmic expression of the β-catenin protein were found in around 19% and 7% of the cells [Figure 3]a and [Figure 3]b. The medium/high membrane expression of β-catenin was seen in around 95% of tumor samples. The membrane expression of β-catenin significantly increased in Stage I + II tumor cells (58.5%, P = 0.0001) followed by a decrease in Stage III + IV tumor cells (37.85%, P = 0.001) [Figure 3]b. On the other hand, nuclear/cytoplasmic expression of β-catenin was significantly increased in Stage I + II tumor cells (23.57%, P = 0.001) and Stage III + IV tumor cells (42.14%, P = 0.0003) [Figure 3]b. Previously, Park et al. revealed that the alteration in β-catenin expression in ampullary carcinoma is a late-onset incident in the adenoma–carcinoma sequence.[29] Previous studies conducted by Yamazaki and Hsu et al. reported that nuclear accumulation of β-catenin was associated with tumor cell proliferation and worse prognosis in ampullary carcinoma patients.[30],[31] In this study, we established that loss of membranous expression or gain of nonmembranous expression of β-catenin was associated with tumor stage. These results propose that altered regulation of the Wnt signaling pathway accumulate β-catenin in the nucleus. The activated β-catenin shuttled into the nucleus, resulting in trans-activation of different target genes (such as CD44) associated with cancer development.[32],[33] Like activation of β-catenin expression (nuclear/cytoplasmic) from normal to the tumor cells at different clinical stages, expression of CD44 receptor in the membrane was low in normal cells (14%) followed by significant increase in Stage I + II tumor cells (30%) and Stage III + IV tumor cells (45%) [Figure 4]a and [Figure 4]b, indicating association with progression of the disease. Similar to our data, Wu et al.[34] observed high/moderate expression of CD44 in 44% of ampullary adenocarcinoma samples with poor patient outcomes. Furthermore, overexpression of CD44 has been shown to be associated with poor survival of patients with pancreatic cancer.[35]

Analysis of the association between epidermal growth factor receptor, insulin-like growth factor 1 receptor, β-catenin, and CD44

Among the samples, high expression of EGFR was seen in 64% (9/14) of the samples along with co-expression of IGF1R in 77.8% (7/9) of samples [Table 2], indicating their association in this tumor. Overexpression of EGFR and IGF1R has been reported in a subset of ampullary adenocarcinoma.[7] The correlations between the expression of EGFR/IGF1R and the expression of β-catenin in patients with PC have not been previously reported. We have seen an association of high expression of EGFR/IGF1R with high β-catenin (nuclear/cytoplasmic) expression in 71.4% (5/7) of PC samples [Table 2]. Further, to understand the association of β-catenin with EGFR and IGF1R, linear regression was done. Results revealed that increased expression of β-catenin of the tumors significantly correlated with high expression of EGFR and IGF1R [Figure 5]a. This might be due to the stabilization of β-catenin and enhanced β-catenin nuclear accumulation. It has been suggested that receptor tyrosine kinases (RTKs) could promote the accumulation of β-catenin in the nuclei of different types of cancer.[36],[37],[38] Furthermore, EGFR binds to the core region of β-catenin and induces phosphorylation of tyrosine in different types of carcinoma.[39] Another RTK, IGF1R also promotes β-catenin stability and nuclear localization, suggesting that it as an important downstream molecule of IGF1R signaling.[40] Interestingly, high expression of activated β-catenin showed an association with high CD44 expression in 62.5% (5/8) of PC samples [Table 2]. This might be due to transcriptional upregulation CD44 by activated β-catenin. In addition, our linear regression study showed a significant association of β-catenin with CD44 in tumor samples [Figure 5]b. The association of nuclear β-catenin expression with the expression of CD44 in breast cancer has been reported.[41]
Figure 5: (a) Graphical representation showing the association of β-catenin (nuclear/cytoplasmic) with epidermal growth factor receptor and insulin-like growth factor 1 receptor expression in PC. (b) Graphical representation showing the association of β-catenin (nuclear/cytoplasmic)-CD44 expression in PC. Y-axis represents the percentage of cells showing the expression of these proteins. The horizontal line in each box represents the median value. The association among different protein expression was evaluated by Pearson's correlation coefficient® (linear regression)

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Table 2: Epidermal growth factor receptor, insulin-like growth factor 1 receptor, beta-catenin, and CD 44 expression in periampullary cancer samples

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  Conclusion Top


Our data revealed the interplay of EGFR, IGF1R, β-catenin, and CD44 expressions in the development of PC. This might have implications in diagnosis, prognosis, and proper therapeutic intervention of the disease. However, our outcomes were gained in a small number of PC samples and further studies are required with a large number of PC samples in this regard.

Acknowledgments

Authors are thankful to the Director of CNCI, Kolkata, India, for his kind support.

Financial support and sponsorship

This work was supported by the Science and Engineering Research Board, India (PDF/2017/002715 to B. Bankura), University Grant Commission, India (21/12/2014 (ii) EU-V to B. Chakraborty) and NASI Senior Scientist Platinum Jubilee Fellowship 2020 ( awarded to Dr. C. K. Panda).

Conflicts of interest

There are no conflicts of interest.



 
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