Bladder Cancer - Molecular Analyte Profiling Of Early Events & Tissue Conditioning Following Intravesical Bacillus Calmette-Guerin Therapy

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 08 Jun 2009 - 1:00 PDT

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UroToday.com - Since the work of Morales et al. in 1976, BCG therapy has been the standard of care for superficial transitional cell carcinoma. Although it has been shown that BCG instillations triggers Th1-mediated responses in patients, the precise mechanism(s) leading to the observed anti-tumoral response remain(s) unknown. More importantly, there are currently defined biomarkers for monitoring the response to BCG. This is particularly relevant as 30-40% of the patients fail to respond to intravesical therapy or relapse within the 5 years. In our recently published study, we investigated the molecular and cytometric profile of the immune response of 17 patients undergoing BCG therapy, and provide the first systemic evaluation of the innate response to intravesical BCG.

In this observational clinical study, we showed that multiple instillations of BCG lead to a prime/boost response. We identified 36 significant molecules in the urine at the third instillation compared to the initial treatment. Of note, our work is the first to identify MIG, IL-16, ENRAGE, MPO, ENA-78, RANTES, MMPs and IL-1RA as locally produced molecules. We also defined a new class of proteins induced by BCG instillation: plasma proteins that leak into the urine. In fact, the presence of plasma proteins in the urine suggests micro-vascular breaks, with the boosted response at the third instillation supporting our hypothesis for increased vascularization of the bladder mucosa. Indeed, several of the analytes identified in the urine are pro-angiogenic including VEGF, IL-8, ENA-78 and MCP-1. In addition, MMP-3 and MMP-9 facilitate tissue remodeling and promote neovascularization. While it is not part of routine care to visualize the bladder wall during BCG therapy, we were able to obtain cytoscopic images before BCG and 6 weeks after the end of the treatment course (Fig. 1). These images demonstrate the considerable increase in the capillary bed of the mucosa after the therapy. With more blood flow through the tissue, the same dose of BCG may trigger a more rapid and more robust immune infiltration. Some data showed that although BCG induces pro-angiogenic molecules at the early stages of therapy, there are also some anti-angiogenic substances produced during the continuation of the therapy up to 6 weeks. Indeed, in our study we do detect some anti-angiogenic molecules like IP-10, IL-1ra and TIMP-1 showing the complex balance between pro- and anti-angiogenic molecules that is engaged in the bladder mucosa following the instillation.

Using cytometric screens, we defined the cellular infiltrates induced by BCG instillation. To integrate these findings, we mapped the observed analytes to their cell sources and performed intracellular cytokines analysis on peripheral mononuclear cells or purified cells of healthy donors stimulated by BCG. We found for instance that monocytes were robust sources of GM-CSF, IL1Ra, MIG, IL-10, IL-6, IL-8, TNFa, MIP-1b and IL-1b and lymphocytes were sources of GM-CSF, IL-8, IFNg, TNFa and MIP-1b.

Thus these data offer a first generation map of the early inflammatory response to BCG therapy, and provide in vivo information concerning the ability to sensitize the tissue microenvironment to enhance innate responses. In conclusion, weekly dosing of BCG is an interesting and important example of how to increase the innate response by what seems to be an intermittent acute inflammation involving a time-dependent participation of pro-angiogenic and anti-angiogenic substances.

Written by Aurélie Bisiaux and Matthew L. Albert, et al. as part of Beyond the Abstract on UroToday.com.

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