Cripto-1 expression in patients with clear cell renal cell carcinoma is associated with poor disease outcome

Xue, Yi-Jun; Chen, Song-Ning; Chen, Weiguang; Wu, Gengqing; Liao, Yijie; Xu, Jiacheng; Tang, Hao; Yang, Sen; He, Shui-Yong; Luo, Yunfei; Wu, Zhihui; Huang, Haiwen

doi:10.1186/s13046-019-1386-6

Cited by 20 publications

(22 citation statements)

References 52 publications

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“…With all this data taken together, we conclude that CRIPTO serum levels are correlated with tumor burden, suggesting that CRIPTO levels mirror patient progression and resistance to treatment. Our findings are consistent with other studies performed in clear cell renal cell carcinoma patients who underwent nephrectomies and had remarkably decreased levels of serum CRIPTO, indicating that CRIPTO levels were reflecting the tumor burden of the patients [36].…”

Section: Discussionsupporting

confidence: 93%

“…Indeed, there recently has been increased interest in CRIPTO serving as a prognostic biomarkernot just in lung cancer, but also in various other cancer types [32]. It has recently been discovered that CRIPTO serum levels were higher in patients with clear cell renal cell carcinoma than healthy controls, and that CRIPTO levels were significantly correlated with grade, tumor size, and TNM stage [36]. High CRIPTO expression was also significantly associated with prostate-specific antigen levels, Gleason score, and lymph node metastasis in prostate cancer [37].…”

Section: Discussionmentioning

confidence: 99%

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Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

et al. 2020

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Background: Adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC) and often harbors oncogenic driver mutations in the epidermal growth factor receptor (EGFR). Osimertinib (AZD9291), a third generation EGFR TKI, has replaced earlier generation EGFR TKIs for first line treatment of EGFR mutant lung cancer due to its improved overall survival, longer progression free survival, and better tolerability compared to earlier generation inhibitors. However, like earlier generation EGFR TKIs, only about two thirds of patients respond, indicating an unknown mechanism of intrinsic resistance for the non-responders. We previously identified overexpression of CRIPTO as a potential mechanism of intrinsic resistance to EGFR TKIs of first and second generation. Objective: To determine if CRIPTO could promote drug resistance against the third generation EGFR-TKIs osimertinib. We also wanted to investigate whether this resistance was conferred by both membrane bound and secreted CRIPTO. Finally, we wanted to explore the potential of secreted CRIPTO as a non-invasive biomarker for EGFR-TKI resistance. Materials and methods: HCC827 and H1975, EGFR mutant non-small cell lung carcinoma (NSCLC) cell lines, were transfected with wildtype CRIPTO, two secreted variants of CRIPTO, a membrane only version of CRIPTO, and the mock backbone vector as the control. Western blotting, immunoprecipitation, and in vitro viability experiments were performed. In vivo work was carried out in athymic nude mice; 2 × 10 6 CRIPTO overexpressing HCC827 cells were implanted per mouse. EGFR mutant NSCLC patient blood samples were collected before treatment with and EGFR-TKI, during response while on treatment, and at progression while on treatment. Results: Although both membrane bound and secreted CRIPTO forms were able to activate downstream pathways such as SRC, CRIPTO was unable to elicit resistance towards osimertinib in vitro or in vivo. CRIPTO serum levels in mice were higher in larger xenograft tumors. Furthermore, CRIPTO serum levels were higher in patients with progressing lung cancer when compared to their CRIPTO serum levels during EGFR-TKI response. Conclusions: CRIPTO does not cause resistance against third generation EGFR-TKI osimertinib. CRIPTO levels in serum might be a potentially useful biomarker for tumor burden in NSCLC patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

et al. 2020

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“…In previous studies, Cripto-1 has been detected at the mRNA or protein levels in tissues of several human solid cancers. Furthermore, Cripto-1 protein levels are also increased in serum/plasma obtained from patients with glioblastoma ( 32 ), renal cell carcinoma ( 33 ), colon cancer and breast cancer ( 34 ). In the present study, Cripto-1 levels were quantitatively determined in the exosomes of serum samples and showed increased levels in PHCCA patients compared to cholangitis patients and healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Exosomal Cripto-1 Serves as a Potential Biomarker for Perihilar Cholangiocarcinoma

Zhang

et al. 2021

Front. Oncol.

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Perihilar cholangiocarcinoma (PHCCA) has a poor prognosis, mainly due to diagnosis at an advanced stage. Cripto-1 functions as an oncogene and is highly expressed in several human cancers, however, its clinical application in PHCCA is poorly understood. Herein, we identified that Cripto-1 was released by PHCCA cells via exosomes in vitro and in vivo. Furthermore, an ELISA method was developed to detect exosomal Cripto-1 in the serum of 115 PHCCA patients, 47 cholangitis patients and 65 healthy controls, and it was found that exosomal Cripto-1 was increased in PHCCA patients and associated with metastasis. Compared with traditional serum tumor markers, CA19-9 and CEA, exosomal Cripto-1 demonstrated a larger area under ROC curve for PHCCA diagnosis. The cutoff value of exosomal Cripto-1 was 0.82, achieving a sensitivity of 79.1% and a specificity of 87.5%. As expected, exosomal Cripto-1 levels in immunohistochemically Cripto-1-high cases were significantly elevated compared to in Cripto-1-low cases. When measured 1-week postoperatively, Cripto-1 levels decreased on average from 1.25(0.96-3.26) to 0.85(0.62-1.82). Immunohistochemistry analysis showed Cripto-1 expression was negatively correlated with E-cadherin and was an independent prognostic biomarker for poor survival in PHCCA patients. In conclusion, exosomal Cripto-1 in sera can reflect its expression in the tissue of PHCAA patients and has the potential be a non-invasive biomarker for diagnosis and prognosis of PHCCA.

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“…Additionally, Cripto-1 promotes EMT in ccRCC cells by activating the Wnt/β-catenin signaling pathway both in vitro and in vivo. Indeed, overexpression of Cripto-1 decreased E-cadherin expression and increased the expression of Vimentin, N-cadherin, β-catenin, ZEB-1, and Snail, as well as the matrix metalloproteinases (MMP-2 and MMP-9) that are involved in tumor invasion and metastasis due to their role in degrading the extracellular matrix [60].…”

Section: Renal Cancermentioning

confidence: 99%

Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells

Arnouk

Yum

Shah

2021

IJMS

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Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1’s role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients.

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Cripto-1 expression in patients with clear cell renal cell carcinoma is associated with poor disease outcome

Cited by 20 publications

References 52 publications

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

Serum CRIPTO does not confer drug resistance against osimertinib but is an indicator of tumor burden in non-small cell lung cancer

Exosomal Cripto-1 Serves as a Potential Biomarker for Perihilar Cholangiocarcinoma

Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells

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