Synchronous vascular endothelial growth factor protein profiles in both tissue and serum identify metastasis and poor survival in colorectal cancer

Yeh, Chien Chih; Shih, Li Jane; Chang, Junn Liang; Tsuei, Yi Wei; Wu, Chang Chieh; Hsiao, Cheng–Wen; Chuu, Chih‐Pin; Kao, Ying-Jer

doi:10.1038/s41598-019-40862-6

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Tumor cells could contribute to an elevated level of VEGF-A in more advanced CRC stages. Increased levels of VEGF-B in stage III and VEGF-D in stages III and IV [ 34 ] could indicate the importance of angio- and lymphangiogenesis processes in advanced disease, contributing to immune escape and formation of metastasis, as supported by recent literature reports.…”

Section: Reviewmentioning

confidence: 80%

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

Czajka-Francuz

Cisoń-Jurek

Czajka

et al. 2021

IJMS

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Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients’ prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.

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Section: Reviewmentioning

confidence: 80%

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

Czajka-Francuz

Cisoń-Jurek

Czajka

et al. 2021

IJMS

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“…Early studies have illustrated the effect of TIPE on the regulation of VEGFR2 in breast cancer metastasis [19]. Recent studies have found that the presence of VEGFR protein in tissues and serum is associated with CRC metastasis [33]. Therefore, although there are data stating that TIPE and VEGFR2 are involved in the metastasis processes of most cancers, their involvement in CRC angiogenesis and the mechanisms involved remain elusive.…”

Section: Introductionmentioning

confidence: 99%

TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer

Zhong

Qiu

et al. 2020

Int. J. Biol. Sci.

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Background: Metastasis is the leading cause of death in colorectal cancer (CRC) patients. It is regulated mainly by tumor cell angiogenesis, and angiogenesis is caused by the binding of vascular endothelial growth factor (VEGF) to vascular endothelial growth factor receptor 2 (VEGFR2). Tumor necrosis factor--induced protein 8 (TNFAIP8, hereto after TIPE) plays an important role in tumorigenesis, development, and prognosis. However, the relationship between TIPE and VEGFR2 in CRC angiogenesis and the mechanism of action remain unknown. Method: In this study, we used quantitative real-time PCR, Western blotting and immunohistochemistry to detect TIPE and VEGFR2 expression in 55 specimens from CRC patients. We also used HCT116 CRC cells and human umbilical vein endothelial cells (HUVECs) for in vitro experiments by stably transducing shTIPE and shRNA control lentivirus into HCT116 cells, detecting VEGFR2 expression after TIPE knockdown and repurposing the culture supernatant as conditioned medium to stimulate angiogenesis of HUVECs. In vivo experiments with chicken chorioallantoic membranes (CAMs) and a nude mouse matrix subcutaneous tumor model were performed to validate the effects of TIPE on angiogenesis. Additionally, we analyzed the expression and phosphorylation levels of PDK1 and blocked PDK1 expression using inhibitors to determine whether TIPE-induced changes in VEGFR2-mediated angiogenesis acted via the PI3K-Akt pathway. Results: We found that TIPE and VEGFR2 are highly expressed in CRC and act as oncogenes. TIPE knockdown also downregulated VEGFR2 expression, which resulted in simultaneous inhibition of cell proliferation, cell migration and angiogenesis. Then, in vivo experiments further demonstrated that TIPE promotes angiogenesis in CRC. Finally, we found that TIPE promotes VEGFR2-mediated angiogenesis by upregulating PDK1 expression and phosphorylation and that blocking PDK1 expression can inhibit this process. Conclusion: TIPE promotes angiogenesis in CRC by regulating the expression of VEGFR2, which may be a target for antiangiogenic cancer therapy.

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“…We also demonstrated that plasma VEGFR3 levels were significantly decreased after surgical resection of rectal tumors. Yeh et al recently showed a significant correlation between circulating VEGFR3 levels and expression of VEGFR3 in tumor tissues [ 31 ]. These findings suggest that circulating VEGFR3 emanated from tumor tissues.…”

Section: Discussionmentioning

confidence: 99%

“…While VEGFR3 is primarily expressed in lymphatic endothelial cells, VEGFR3 and its main ligand VEGF-C are expressed in tumor cells of various types of cancer, including colorectal cancer [ 33 ]. Higher expression of VEGFR3 in tumor tissues has been also associated with advanced TNM stages, the occurrence of metastasis, and poor prognosis in colorectal cancer [ 31 , 34 ]. Recent studies have revealed that activation of VEGF-C/VEGFR3 signaling promotes tumor growth and invasion by disrupting the lymphatic endothelial barrier and by recruiting and inducing immunosuppressive tumor-associated macrophages in colorectal cancer [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer

Dayde

Gunther

Hirayama

et al. 2021

Cancers

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The current standard of care for patients with locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (nCRT) followed by total mesorectal excision surgery. However, the response to nCRT varies among patients and only about 20% of LARC patients achieve a pathologic complete response (pCR) at the time of surgery. Therefore, there is an unmet need for biomarkers that could predict the response to nCRT at an early time point, allowing for the selection of LARC patients who would or would not benefit from nCRT. To identify blood-based biomarkers for prediction of nCRT response, we performed in-depth quantitative proteomic analysis of pretreatment plasma from mice bearing rectal tumors treated with concurrent chemoradiation, resulting in the quantification of 567 proteins. Among the plasma proteins that increased in mice with residual rectal tumor after chemoradiation compared to mice that achieved regression, we selected three proteins (Vascular endothelial growth factor receptor 3 [VEGFR3], Insulin like growth factor binding protein 4 [IGFBP4], and Cathepsin B [CTSB]) for validation in human plasma samples. In addition, we explored whether four tissue protein biomarkers previously shown to predict response to nCRT (Epidermal growth factor receptor [EGFR], Ki-67, E-cadherin, and Prostaglandin G/H synthase 2 [COX2]) also act as potential blood biomarkers. Using immunoassays for these seven biomarker candidates as well as Carcinoembryonic antigen [CEA] levels on plasma collected before nCRT from 34 patients with LARC (6 pCR and 28 non-pCR), we observed that levels of VEGFR3 (p = 0.0451, AUC = 0.720), EGFR (p = 0.0128, AUC = 0.679), and COX2 (p = 0.0397, AUC = 0.679) were significantly increased in the plasma of non-pCR LARC patients compared to those of pCR LARC patients. The performance of the logistic regression model combining VEGFR3, EGFR, and COX2 was significantly improved compared with the performance of each biomarker, yielding an AUC of 0.869 (sensitivity 43% at 95% specificity). Levels of VEGFR3 and EGFR were significantly decreased 5 to 7 months after tumor resection in plasma from 18 surgically resected rectal cancer patients, suggesting that VEGFR3 and EGFR may emanate from tumors. These findings suggest that circulating VEGFR3 can contribute to the prediction of the nCRT response in LARC patients together with circulating EGFR and COX2.

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Synchronous vascular endothelial growth factor protein profiles in both tissue and serum identify metastasis and poor survival in colorectal cancer

Cited by 9 publications

References 34 publications

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

Systemic Interleukins’ Profile in Early and Advanced Colorectal Cancer

TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer

Identification of Blood-Based Biomarkers for the Prediction of the Response to Neoadjuvant Chemoradiation in Rectal Cancer

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