The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure11The first author has a PhD Grant (SFRH/BD/43399/2008) and J.A.F. has a Postdoctoral Grant (SFRH/BPD/66288/2009) from FCT—Fundação para a Ciência e Tecnologia, co-financed by European Social Fund (ESF) under Human Potential Operation Programme (POPH) from National Strategic Reference Framework (NSRF). We thank to LPCC, Portuguese League Against Cancer (NRNorte) for their sup

Lima, Luís; Oliveira, Daniela; Tavares, Ana; Amaro, Teresina; Cruz, Ricardo Pedrini; Oliveira, Maria José; Ferreira, José Alexandre; Santos, Lúcio Lara

doi:10.1016/j.urolonc.2013.10.012

Cited by 70 publications

(34 citation statements)

References 29 publications

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“…We also observed the strongest CD68+ and CD163+ TAM infiltration in the tumor stroma and lamina propria. An increased density of M2-polarized macrophages in the stroma, but not in tumor cells, was related to BCG failure and a 2.6-fold higher risk of recurrence [52–53]. Conversely, CD68+ TAMs in stroma or within tumor nests were found to have no effect on the outcome of BCG [54].…”

Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

et al. 2016

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Although Bacillus Calmette-Guérin (BCG) is the most successful immunotherapy for high-risk non-muscle-invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. New biomarkers are important to identify patients who will benefit most from BCG during a worldwide BCG shortage. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using monoclonal antibodies to tumor-associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). Cell densities in the lamina propria without invasion, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium were calculated. Twenty-nine (72.5%) of 40 patients were classified as BCG responders after a mean follow-up of 35.3 months. A statistically significant association was observed for BCG failure with low density of CD4+ and GATA3+ T-cells, and increased expression of FOXP3+ and CD25+ regulatory T-cells (Tregs) as well as CD68+ and CD163+ TAMs. Survival analysis demonstrated prolonged recurrence-free survival (RFS) in patients with an increased count of CD4+ and GATA3+ T-cells. TAMs, Tregs and T-bet+ T-cells were inversely correlated with RFS. Thus, the tumor microenvironment seems to influence the therapeutic response to BCG, permitting an individualized treatment.

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Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

et al. 2016

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“…Significant amount of evidences support the notion that hypoxia enhances the malignant nature of bladder cancer cells by promoting tumor cell migration, invasion, chemoresistance, metastasis and immune modulation [28, 30, 42–44]. Furthermore, many of the transcriptome remodeling events underlying these transformations are mediated by HIF-1α [45].…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidences suggest that hypoxia plays a key role in bladder cancer chemoresistance, invasion and dissemination, which warrants future comprehensive studies towards novel biomarkers and innovative therapeutics [27–30]. Based on these observations, we have devoted to the identification of the most stable reference genes out of a panel of seven candidates, namely Hypoxanthine phosphoribosyltransferase-1 (HPRT) , ACTB , 18 ribosomal RNA ( 18S) , GAPDH , TATA-binding protein ( TBP) , Beta-2 microglobulin ( B2M) , and Succinate dehydrogenase complex flavoprotein subunit A ( SDHA ), to address the effect of hypoxia in the context of bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

Reference Genes for Addressing Gene Expression of Bladder Cancer Cell Models under Hypoxia: A Step Towards Transcriptomic Studies

et al. 2016

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Highly aggressive, rapidly growing tumors contain significant areas of hypoxia or anoxia as a consequence of inadequate and/or irregular blood supply. During oxygen deprivation, tumor cells withstand a panoply of adaptive responses, including a shift towards anaerobic metabolism and the reprogramming of the transcriptome. One of the major mediators of the transcriptional hypoxic response is the hypoxia-inducible factor 1 (HIF-1), whose stabilization under hypoxia acts as an oncogenic stimulus contributing to chemotherapy resistance, invasion and metastasis. Gene expression analysis by qRT-PCR is a powerful tool for cancer cells phenotypic characterization. Nevertheless, as cells undergo a severe transcriptome remodeling.in response to oxygen deficit, the precise identification of reference genes poses a significant challenge for hypoxic studies. Herein, we aim to establish the best reference genes for studying the effects of hypoxia on bladder cancer cells. Accordingly, three bladder cancer cell lines (T24, 5637, and HT1376) representative of two distinct carcinogenesis pathways to invasive cancer (FGFR3/CCND1 and E2F3/RB1) were used. Additionally, we have explored the most suitable control gene when addressing the influence of Deferoxamine Mesilate salt (DFX), an iron chelator often used to avoid the proteasomal degradation of HIF-1α, acting as an hypoxia-mimetic agent. Using bioinformatics tools (GeNorm and NormFinder), we have elected B2M and HPRT as the most stable genes for all cell lines and experimental conditions out of a panel of seven putative candidates (HPRT, ACTB, 18S, GAPDH, TBP, B2M, and SDHA). These observations set the molecular basis for future studies addressing the effect of hypoxia and particularly HIF-1α in bladder cancer cells.

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“…(79) This may be important in UBC because macrophages exist on a continuum from an M1 (inflammatory) to an M2 (pro-tumorigenic) phenotype and the presence of M2 macrophages in the UBC stroma has been associated with BCG immunotherapy failure. (80) CSF1 ligation promotes the skewing of macrophages to the M2 phenotype, so blocking CSF1, or depleting CSF1R expressing cells promotes the development of anti-tumor M1 macrophages, and has been shown to be efficacious in animal studies. (81) A relatively specific small molecule inhibitor of CSF1R (PLX3397, Plexxikon) is now undergoing clinical evaluation in a Phase I/II trial in combination with pembrolizumab in patients with advanced cancers including UBC (NCT02452424, Table 1).…”

Section: On the Horizonmentioning

confidence: 99%

New Strategies in Bladder Cancer: A Second Coming for Immunotherapy

Ghasemzadeh

Bivalacqua

Hahn

et al. 2016

Clinical Cancer Research

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Urothelial bladder cancer (UBC) remains one of the most common and deadly cancers worldwide, and platinum based chemotherapy, which has been the standard of care in metastatic bladder cancer, has had limited success in improving outcomes for patients. The recent development and translation of therapeutic strategies aimed at harnessing the immune system has led to durable and prolonged survival for patients with several different cancers, including UBC. In this review, we discuss new findings in bladder cancer immunotherapy, including recent successes with immune checkpoint blockade. We also discuss therapeutic cancer vaccines, and highlight several additional immunotherapy modalities in early stages of development.

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Abstract: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163(+) macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.

Cited by 70 publications

References 29 publications

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

Reference Genes for Addressing Gene Expression of Bladder Cancer Cell Models under Hypoxia: A Step Towards Transcriptomic Studies

New Strategies in Bladder Cancer: A Second Coming for Immunotherapy

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