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Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study aimed to examine the role of CD44 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analyzed the effect of CD44 knockdown on sunitinib resistance in RCC cell lines using WST-1 assays. CD44 expression in mRCC patients treated with first-line sunitinib was determined by immunohistochemistry. We validated the findings of this study by in silico analysis., Results: CD44 knockdown increased sensitivity to sunitinib. Immunohistochemical analysis revealed that 19 (34.5%) of 55 mRCC cases were positive for CD44. CD44-positive cases were associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, high CD44 expression was significantly associated with poor PFS after sunitinib but not after avelumab + axitinib therapy., Conclusion: CD44 is involved in sunitinib resistance and may be a promising marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC., Results: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan-Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment., Conclusion: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Targeted receptor tyrosine kinase inhibitor (TKI) is a standard treatment in advanced renal cell carcinoma (RCC). However, the role of PTEN in TKI resistance remains poorly understood. We aimed to determine the functional role of PTEN knockout and analyse the predictive significance of PTEN expression for TKI treatment in RCC., Materials and Methods: We developed PTEN knockout cells in RCC cell lines using the CRISPR-Cas9 system and analysed the effect of PTEN knockout on spheroid formation and resistance to sunitinib and sorafenib., Results: PTEN knockout promoted spheroid formation and decreased sunitinib/sorafenib sensitivity in RCC cell lines. PTEN immunohistochemistry in 74 metastatic RCCs treated with sunitinib and sorafenib revealed negative PTEN expression in 23% of samples. Kaplan-Meier analysis showed a significant association of negative PTEN expression with poor progression-free survival in metastatic RCC treated with sunitinib and sorafenib (p=0.024) or sunitinib alone (p=0.009)., Conclusion: PTEN may be a biomarker and therapeutic target in patients with metastatic RCC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Colorectal adenoma is well known as a precursor lesion of colorectal adenocarcinoma (ADC). We recently reported the significance of CD204 (+) tumor-associated macrophages (TAMs), a vital component of the tumor microenvironment, in the carcinoma development of gastric adenoma. The aim of the present study was to clarify the roles of TAM in the malignant transformation of colorectal adenoma., Materials and Methods: We immunohistochemically assessed the TAM number in 88 tubular or tubulovillous adenomas that were classified into L (low-grade adenomas) or H (high-grade adenomas)., Results: Larger adenoma size, higher frequency of villous structure, loss of proliferation polarity, p53 expression, larger TAM numbers and larger microvessel density (MVD) were detected in Group H than in Group L adenomas. Positive relations were observed between TAM and MVD, proliferation polarity and the expression of p53., Conclusion: CD204 (+) TAM is a novel component in the malignant transformation of colorectal adenoma., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Gastric cancer (GC) is one of the most common malignancies worldwide. Gremlin1 is an antagonist of bone morphogenetic proteins that plays a critical role in several biological processes including cancer biology., Materials and Methods: We immunohistochemically examined the expression and distribution of Gremlin1 in non-neoplastic gastric mucosa in a series of 159 GC cases., Results: Among 159 GC primary tumors, 59 (37%) were positive for Gremlin1. Gremlin1-negative GC cases showed significantly more advanced clinicopathologic factors and a trend toward intestinal-type GC. Gremlin1 expression was also frequently observed in MUC5AC-positive and G-type GC cases. Gremlin1-negative GCs had a poorer survival rate than Gremlin1-positive GCs (p=0.002). Univariate and multivariate analyses revealed that Gremlin1 expression is an independent predictor of survival in GCs., Conclusion: These results indicate that Gremlin1 could be involved in GC progression and may be a good marker of long-term survival in GC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Renal cell carcinoma (RCC) is one of the most common types of cancer in developed countries. Bone marrow stromal cell antigen 2 (BST2) gene, which encodes BST2 transmembrane glycoprotein, is overexpressed in several cancer types. In the present study, we analyzed the expression and function of BST2 in RCC., Materials and Methods: BST2 expression was analyzed by immunohistochemistry in 123 RCC cases. RNA interference was used to inhibit BST2 expression in a RCC cell line., Results: Immunohistochemical analysis showed that 32% of the 123 RCC cases were positive for BST2. BST2 expression was positively associated with tumour stage. Furthermore, BST2 expression was an independent predictor of survival in patients with RCC. BST2 siRNA-transfected Caki-1 cells displayed significantly reduced cell growth and invasive activity relative to negative control siRNA-transfected cells., Conclusion: These results suggest that BST2 plays an important role in the progression of RCC. Because BST2 is expressed on the cell membrane, BST2 is a good therapeutic target for RCC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Oesophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) are common types of human cancer. Spheroid colony formation is used to characterize cancer stem cell (CSCs). In the present study, we analyzed the significance of kinesin family 11 (KIF11 in human ESCC and CRC., Materials and Methods: Expression of KIF11 in 105 ESCC and 100 CRC cases was determined using immunohistochemistry. RNA interference was used to inhibit KIF11 expression in ESCC and CRC cell lines., Results: In total, 61 out of 105 (58%) ESCC and 62 out of 100 (62%) CRC cases were positive for KIF11. Expression of KIF11 was not associated with any clinicopathological characteristics. Both the number and size of spheres produced by from TE-5 ESCC cells and DLD-1 CRC cells were significantly reduced upon KIF11 siRNA transfection compared to negative control siRNA transfection., Conclusion: These results indicate that KIF11 plays an important role in CSCs of ESCC and CRC., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)