Differential expression of claudin-2 in normal human tissues and gastrointestinal carcinomas

Aung, Phyu P.; Mitani, Yoshitsugu; Yukitoshi, Sanada; Nakayama, Hirofumi; Matsusaki, Keisuke; Yasui, Wataru

doi:10.1007/s00428-005-0120-2

Cited by 64 publications

(50 citation statements)

References 22 publications

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“…In our sample set, we found weak or moderate claudin-2 positivity in liver metastases of colorectal and pancreatic cancers. Obvious claudin-2 expression has already been described in 25.3% of colorectal (Aung et al 2006) and 45% of pancreatic adenocarcinomas (Borka et al 2007). Thus, claudin-2 may not only participate in the carcinogenesis of these tumors but may also contribute to a metastatic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Distinct Claudin Expression Profiles of Hepatocellular Carcinoma and Metastatic Colorectal and Pancreatic Carcinomas

Holczbauer

Gyöngyösi

Lotz

et al. 2013

J Histochem Cytochem.

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Tight junction proteins, including claudins, are often dysregulated during carcinogenesis and tumor progression. Moreover, the claudin expression pattern usually varies between different tumor entities. We aimed to investigate claudin expression profiles of primary and metastatic liver malignancies. We analyzed claudin-1, -2, -3, -4, and -7 expression by quantitative immunohistochemistry and real-time RT-PCR, respectively. Twenty hepatocellular carcinomas (HCCs) and liver metastases of 20 colorectal adenocarcinomas (CRLMs) and 15 pancreatic adenocarcinomas (PLMs) were studied together with paired surrounding non-tumorous liver samples and 5 normal liver samples. Strong claudin-3 and -7 immunohistochemical positivities were detected in CRLM samples, each with significantly stronger staining when compared with HCC and PLM groups. Claudin-1 protein was found highly expressed in CRLM, in contrast to lower expression in PLM and HCC. CRLMs and PLMs also were strongly positive for claudin-4, while being virtually undetectable in HCC. Claudin-2 showed strong positivity in non-tumorous liver tissue, whereas significantly weaker positivity was observed in all tumors. Differences in mRNA expression were mostly similar to those found by immunohistochemistry. In conclusion, HCC and both CRLM and PLM display distinct claudin expression profiles, which might provide better understanding of the pathobiology of these lesions and might be used for differential diagnosis.

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Section: Discussionmentioning

confidence: 99%

Distinct Claudin Expression Profiles of Hepatocellular Carcinoma and Metastatic Colorectal and Pancreatic Carcinomas

Holczbauer

Gyöngyösi

Lotz

et al. 2013

J Histochem Cytochem.

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“…Moreover, claudin-2 has been observed for gastric carcinomas and colorectal cancer, which are both highly metastatic to the liver (1,15,21). It is conceivable that claudin-2 expression is selected for in primary liver cancer and in solid cancer cells that display a propensity to metastasize to the liver.…”

Section: Discussionmentioning

confidence: 99%

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

Tabariès

Dupuy

Dong

et al. 2012

Molecular and Cellular Biology

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hWe previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. Metastatic tumor cells must overcome numerous barriers in order to successfully disseminate to distant organs. The metastatic cascade consists of multiple steps, including local tumor cell migration, invasion and intravasation into the lymphatic system or bloodstream, survival in the circulation, adhesion/extravasation at the metastatic site, evasion of immunosurveillance, and eventual growth in a foreign microenvironment (29,30). Of these numerous steps, interactions between tumor cells and resident cells within the metastatic microenvironment represent the most important determinants contributing to the ability of cancer cells to metastasize to specific organs (14,24).The liver represents a common site of metastasis for solid cancers and represents the third most common site for breast cancer metastasis (12). Unique structural features of the liver, including the open fenestrae that characterize the sinusoidal endothelium coupled with the lack of an organized subendothelial basement membrane, have a great impact on tumor interactions within the hepatic microenvironment. Early in vivo electron microscopy studies revealed that breast cancer cells, upon seeding the liver, can extend cellular projections through the fenestrated endothelium into the space of Disse, making direct contact with hepatocytes (36). Subsequent in vitro studies revealed that breast cancer cells form electron-dense structures at points of contact between hepatocytes, which are reminiscent of tight-junctional complexes (37). The importance of cancer cell-hepatocyte interactions has been reinforced by the observation that colorectal cancer cells also interact directly with hepatocytes during liver metastasis (31, 32). However, the mechanisms underlying these heterotypic cell-cell interactions are largely unexplored.Claudins are key components within tight junctions, and they participate in homo-and hete...

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“…Altered expression of claudins has been reported in several malignant tumors, including those of the ovary [22,35,36] , prostate [23] , breast [24,37] , pancreas [25] , colorectum [26,38] and stomach [39] in comparison with the corresponding normal tissues; however, little is known about the mechanism through which claudins control cancer cell behavior. A previous study reported that 75% of the stage II CRCs exhibited elevated levels of claudin-1 expression, while decreased claudin-1 expression was directly associated with higher tumor grade, recurrence and poor survival [26] .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Expression of Claudin-4 in Human Colorectal Cancer: Decreased Claudin-4 Expression at the Invasive Front Correlates Cancer Invasion and Metastasis

et al. 2007

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Objective: Claudin-4 plays a key role in constructing the tight junction (TJ), and altered claudin-4 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin-4 in colorectal cancers (CRCs). The aim of this study is to investigate the significance of claudin-4 expression in CRC and its association with clinicopathological factors. Methods: The levels of claudin-4 expression in a total of 129 CRCs and 44 metastatic tumors were examined by immunohistochemistry. A small interfering RNA (siRNA)-mediated claudin-4 knockdown examination was also conducted to assess the biological role(s) of claudin-4 in cultured cells. Results: Expression of claudin-4 at the intercellular membrane was well preserved at the surface of the tumor; however, decreased claudin-4 expression was detected in 57% of CRCs, particularly at the invasive front. Interestingly, decreased claudin-4 expression was detected in metastatic lesions of CRC. The siRNA-mediated claudin-4 knockdown in SW480 claudin-4-positive CRC cells upregulated cell motility, whereas no significant change was detected in cell proliferation. Conclusions: These observations suggested that disruption of claudin-4-mediated TJ construction enhances cancer cell invasion and metastasis in human CRC. Claudin-4 might be a good biomarker for diagnosing the risk of distant metastasis.

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Differential expression of claudin-2 in normal human tissues and gastrointestinal carcinomas

Cited by 64 publications

References 22 publications

Distinct Claudin Expression Profiles of Hepatocellular Carcinoma and Metastatic Colorectal and Pancreatic Carcinomas

Distinct Claudin Expression Profiles of Hepatocellular Carcinoma and Metastatic Colorectal and Pancreatic Carcinomas

Claudin-2 Promotes Breast Cancer Liver Metastasis by Facilitating Tumor Cell Interactions with Hepatocytes

Heterogeneous Expression of Claudin-4 in Human Colorectal Cancer: Decreased Claudin-4 Expression at the Invasive Front Correlates Cancer Invasion and Metastasis

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