Expression of GLUT4 and FAP in urothelial bladder carcinoma: correlation with angiogenesis and clinicopathological characteristics

Abstract

Background Urothelial carcinoma (UC) is the most common type of bladder cancer. Glucose transporter 4 (GLUT4) is one of glucose transporter proteins’ family which facilitates glucose transport inside the cells. It was found to be overexpressed in several malignant tumors. Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells located adjacent to cancer cells and are considered one of the most important tumor stromal cells. They have been associated with enhancing tumor growth and invasion. GLUT4 expression in malignant epithelial cells and fibroblast activation protein (FAP) expression in CAFs of UC in relation to angiogenesis and clinicopathological characteristics are studied in this work. Materials and methods The study was carried out on 72 paraffin blocks of UC (27 radical cystectomies and 45 transurethral resections). Immunohistochemical staining was performed with GLUT4, FAP, and CD34 antibodies. Expression of GLUT4 and FAP was classified according to the staining intensities and percentages into low and high groups. CD34-stained microvessels’ mean count in five microscopic fields (×200) was taken as the microvessel density (MVD). Results GLUT4 overexpression was detected in 32 UC. It was significantly associated with high-grade tumors, advanced primary tumor (pT) stage, lymphovascular invasion (LVI), and regional lymph node invasion. High FAP expression was appreciated in 27 UC and was significantly linked to LVI and advanced TNM staging. Intratumor MVD significantly increased in UC with muscle invasion, LVI, and regional lymph node and/or distant metastasis. A significant positive correlation between GLUT4, FAP expression, and MVD was found. Conclusion GLUT4 and FAP expression was significantly associated with increased intratumor MVD and adverse clinicopathological factors.

N-myc downstream–regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma

“…In the current study, high intra-tumor MVD was associated with higher tumor grade, stage, and lymphovascular invasion. This finding is in agreement with previous studies in urothelial carcinoma [ 24 , 25 ] suggesting that assessment of tumor vascularity may be useful in predicting patients’ prognosis and selecting those who will benefit from anti-angiogenic therapies [ 25 ]. It has been reported that the initiation of angiogenesis occurs when the proangiogenic factors (e.g., vascular endothelial growth factor) surpass anti-angiogenic factors which result in progressive tumor growth [ 26 ].…”

“…Angiogenesis is a multistep dynamic process, which is characterized by the proliferation, migration, and differentiation of endothelial cells into new capillaries. MVD is used to evaluate tumor vasculature using endothelial markers [ 24 ]. In the current study, high intra-tumor MVD was associated with higher tumor grade, stage, and lymphovascular invasion.…”

Association of future cancer metastases with fibroblast activation protein-α: a systematic review and meta-analysis

“…After assessing the titles, abstracts, and keywords, 3,391 articles were excluded due to unrelated patient populations, exposures, or outcomes. Additionally, 686 articles that initially met the inclusion criteria were reassessed, and 28 articles ( 4 , 13 – 39 ) were finally included in this meta-analysis. Table 1 shows the articles published between 2007 and 2023.…”

“…Table 1 shows the articles published between 2007 and 2023. Among the studies conducted to determine the association between FAP-α and metastasis, 13 studies were conducted in China ( 4 , 17 , 20 , 26 , 27 , 29 , 31 – 36 , 38 ), three studies in Japan ( 22 – 24 ), three studies in South Korea ( 21 , 25 , 30 ), two studies in Spain ( 16 , 19 ), and seven studies in seven countries such as Sweden ( 15 ), Switzerland ( 18 ), France ( 14 ), Egypt ( 13 ), USA ( 37 ), Germany ( 39 ), and Belgium ( 28 ). The majority of the included studies were designed as cohorts, and the most common methods used for FAP-α detection were immunohistochemistry and Western blotting.…”

An Overview of Angiogenesis in Bladder Cancer

“…HSP47 downregulation suppresses angiogenesis in BC cells. Activation of the ERK pathway and induction of C–C Motif Chemokine Ligand 2 (CCL2) are responsible for HSP47-induced angiogenesis Wang et al [ 73 ] Mettl3 BC cell lines T24 and UMUC-3 Transgenic mice Ablation of Mettl3 in bladder urothelial cells attenuates the oncogenesis and tumour angiogenesis of BC Abd El-Azeem, Ali and El-Shorbagy [ 74 ] GLUT4 BC tissue samples of radical cystectomies and TUR GLUT4 and fibroblast activation protein (FAP) expression is significantly associated with increased intratumour MVD and adverse clinicopathological factors Mori et al [ 75 ] VCAM-1 Preoperative plasma samples Elevated VCAM-1 is associated with aggressive BC. Preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from multimodal therapy Vlachostergios et al [ 76 ] HIF-2 Publicly available next-generation sequencing (NGS) data from muscle-invasive BC cell lines and patient tumour samples from the MSK/TCGA 2020 cohort were interrogated HIF-2-altered BC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes Xia et al [ 77 ] PKM2 Genetically engineered mice BC cell lines RT112, 1376, UMUC3, and T24 and mouse BC cell line MBT2 PKM2 ablation in mouse urothelial cells and/or chemical inhibition of PKM2 reduces complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis Yang et al [ 78 ] Occludin Cell lines T24 and 5637.…”