Identification of Calreticulin as a Prognosis Marker and Angiogenic Regulator in Human Gastric Cancer

Chen, Chiung-Nien; Chang, Cheng-Chi; Su, Ting-En; Hsu, Wen Ming; Jeng, Yung‐Ming; Ho, Ming‐Chih; Hsieh, Fon‐Jou; Lee, Po‐Huang; Kuo, Min-Liang; Lee, Hsinyu; Chang, King‐Jen

doi:10.1245/s10434-008-0243-1

Cited by 117 publications

(103 citation statements)

References 33 publications

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“…In gastric cancer, positive immunohistochemical staining of calreticulin was found to be correlated with high microvessel density, serosal and perineural invasion, lymph node spread, and poor patient survival. 28 Yet, in neuroblastoma, the most common malignancy in infants, positive immunohistochemical staining for calreticulin was correlated with better prognosis and patient survival. 23 Calreticulin was also found to be differentially expressed in colorectal cancer.…”

Section: Discussionmentioning

confidence: 98%

Clinicopathological significance of calreticulin in breast invasive ductal carcinoma

et al. 2010

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Calreticulin is a chaperone protein located in the lumen of the endoplasmic reticulum. The association of calreticulin with pathological conditions such as autoimmune disorders and certain types of cancer have been reported. However, little is known about its role in the pathogenesis of breast cancer. The aim of this study was to determine the expression of calreticulin in vitro and correlate its expression levels in breast cancer tissue samples with clinicopathological parameters. Calreticulin expression was evaluated in MCF-7 and MDA-MB-231 breast cancer cells by real-time RT-PCR, Western blot, immunohistochemistry, and immunofluorescence staining. Patient tissue microarrays were constructed from 228 breast cancer specimens for immunohistochemical analysis. The in vitro study showed a higher calreticulin expression in more aggressive MDA-MB-231 cells as compared with MCF-7 cells at both mRNA and protein levels. In all, 227 out of 228 breast cancer samples exhibited calreticulin staining in at least 5% of the cancer cells. Calreticulin immunostaining was observed to be localized to the cytoplasm of the cancer cells. Regression analysis of calreticulin immunostaining in the tissue microarrays revealed that its expression was positively correlated to logarithm of (log) tumor size (P ¼ 0.046) and development of distant metastasis (P ¼ 0.017). Multivariate analysis confirmed calreticulin expression as an independent predictor of log tumor size and occurrence of distant metastasis. The data suggest that calreticulin expression is associated with more advanced tumors and is a potential prognostic biomarker.

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Section: Discussionmentioning

confidence: 98%

Clinicopathological significance of calreticulin in breast invasive ductal carcinoma

et al. 2010

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“…CRT has been evaluated as a potential biomarker in several types of cancer including neuroblastoma (40), bladder (41), gastric (42), breast cancer (43), and acute myeloid leukemia (38). CRT has also been reported to be overexpressed in the cytoplasm and at the membrane level of NSCLC cells, and serum level of CRT protein was associated with tumor pathologic grade (44), although the prognostic impact of circulating CRT levels has not been studied.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Expression in Human Non–Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis

et al. 2016

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A high density of tumor-infiltrating mature dendritic cells (DC) and CD8þ T cells correlates with a positive prognosis in a majority of human cancers. The recruitment of activated lymphocytes to the tumor microenvironment, primed to recognize tumor-associated antigens, can occur in response to immunogenic cell death (ICD) of tumor cells. ICD is characterized by the preapoptotic translocation of calreticulin (CRT) from the endoplasmic reticulum (ER) to the cell surface as a result of an ER stress response accompanied by the phosphorylation of eukaryotic initiation factor 2a (eIF2a). We conducted a retrospective study on two independent cohorts of patients with non-small cell lung cancer (NSCLC) to investigate the prognostic potential of CRT. We report that the level of CRT expression on tumor cells, which correlated with eIF2a phosphorylation, positively influenced the clinical outcome of NSCLC. High CRT expression on tumor cells was associated with a higher density of infiltrating mature DC and effector memory T-cell subsets, suggesting that CRT triggers the activation of adaptive immune responses in the tumor microenvironment. Accordingly, patients with elevated CRT expression and dense intratumoral infiltration by DC or CD8 þ T lymphocytes had the best prognosis. We conclude that CRT expression constitutes a new powerful prognostic biomarker that reflects enhanced local antitumor immune responses in the lung.

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“…CRT is a calciumbinding protein that is crucial for many cellular processes (4). High levels of CRT are significantly associated with poor outcome and metastasis in patients with gastric cancer (5), bladder cancer (6), and breast cancer (7,8). Several observations show that CRT overexpression contributes to cancer cell survival, migration, and invasion (9), but the underlying molecular mechanisms are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

Feng

Pan

et al. 2014

Clinical Cancer Research

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Purpose: We previously revealed that the calreticulin (CRT) gene is a candidate oncogene promoting cell migration and invasion and that neuropilin-1 (NRP1) is a possible effector downstream of CRT in esophageal squamous carcinoma cells. This study aims to explore the mechanisms underlying the migration and invasion of esophageal cancer cells regulated by CRT through NRP1.Experimental Design: Quantitative reverse-transcription polymerase chain reaction, Western blot analysis, chromatin immunoprecipitation, and reporter gene assays were used to investigate the relationship between CRT and NRP1. In vitro and in vivo assays were carried out to evaluate the effects of NRP1 on malignant phenotypes of ESCC cells and tumor metastasis in NOD/SCID mice. Immunohistochemistry was performed to analyze the expression of CRT and NRP1 in esophageal squamous cell carcinomas (ESCC).Results: Knockdown of CRT decreased the expression of NRP1. Inhibition of NRP1 reduced ESCC cell motility in vitro and experimental metastasis in vivo. Ectopic expression of NRP1 rescued the defects of cell migration and invasion in CRT-shRNA cells. CRT depletion inhibited STAT5A phosphorylation at the Y694 site via a CaMKII-independent pathway. Moreover, STAT5A directly regulated NRP1 transcription. Knockdown of CRT or NRP1 led to a downregulation of MMP2, MMP9, and FAK. Notably, positive correlation was found between CRT and NRP1 expression in ESCC tissues (P ¼ 5.87 Â 10 À5 ). CRT and NRP1 coexpression was significantly associated with lymph node metastasis (P ¼ 0.025). Conclusions: Our findings suggest that NRP1 is a critical downstream effector of CRT in promoting cell migration and invasion, which might contribute to the metastasis of ESCC.

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Identification of Calreticulin as a Prognosis Marker and Angiogenic Regulator in Human Gastric Cancer

Cited by 117 publications

References 33 publications

Clinicopathological significance of calreticulin in breast invasive ductal carcinoma

Clinicopathological significance of calreticulin in breast invasive ductal carcinoma

Calreticulin Expression in Human Non–Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis

Calreticulin Promotes Migration and Invasion of Esophageal Cancer Cells by Upregulating Neuropilin-1 Expression via STAT5A

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