Urinary Markers in Bladder Cancer: An Update.

Bladder cancer (BC) is ones of the most common cancer worldwide. It is classified in muscle invasive (MIBC) and muscle non-invasive (NMIBC) BC. NMIBCs frequently recur and progress to MIBCs with a reduced survival rate and frequent distant metastasis. BC detection require unpleasant and expensive cystoscopy and biopsy, which are often accompanied by several adverse effects. Thus, there is an urgent need to develop novel diagnostic methods for initial detection and surveillance in both MIBCs and NMIBCs. Multiple urine-based tests approved by FDA for BC detection and surveillance are commercially available. However, at present, sensitivity, specificity and diagnostic accuracy of these urine-based assays are still suboptimal and, in the attend to improve them, novel molecular markers as well as multiple-assays must to be translated in clinic. Now there are growing evidence toward the use of minimally invasive "liquid biopsy" to identify biomarkers in urologic malignancy. DNA- and RNA-based markers in body fluids such as blood and urine are promising potential markers in diagnostic, prognostic, predictive and monitoring urological malignancies. Thus, circulating cell-free DNA, DNA methylation and mutations, circulating tumor cells, miRNA, IncRNA and mRNAs, cell-free proteins and peptides, and exosomes have been assessed in urine specimens. However, proteomic and genomic data must to be validated in well-designed multicenter clinical studies, before to be employed in clinic oncology.

Advances in transient receptor potential vanilloid-2 channel expression and function in tumor growth and progression.

Aim of this review is to study the role of the TRPV2 channel, a member of the TRPV subfamily of TRP channels, in tumor progression. Physiologically, the triggering of TRPV2 by agonists/activators (e.g., growth factors, hormones and cannabinoids), by inducing TRPV2 translocation from the endosome to the plasmatic membrane, inhibit cell proliferation and induce necrosis and/or apoptosis. Thus, loss or alterations of TRPV2 proliferative and apoptotic signals, results in uncontrolled proliferation and augmented resistance to apoptotic stimuli. For example in prostate cancer cells, the TRPV2 activation following lysophospholipid or adrenomedullin stimulation enhances the invasiveness of cancer cells; furthermore, the increased malignancy of castration-resistant prostate cancer cells was associated with enhanced TRPV2 expression, mainly in metastatic prostate cancer cells. In addition, the TRPV2 cellular functions may also to be related to the presence of TRPV2 variants, able to interfere with the physiological functions of normal TRPV2 channels. In this regard, bladder cancer tumors show loss or reduction of a short TRPV2 variant during cancer progression, with increased malignancy and invasiveness. High expression of TRPV2 was also observed more frequently in esophageal squamous cell carcinoma patients with advanced pT stage, lymph node metastasis and advanced pathological stage.

Expression and function of the transient receptor potential ion channel family in the hematologic malignancies.

Transient receptor potential (TRP) channels are important candidates mediating Ca(2+) influx in excitable and nonexcitable cells such as normal and neoplastic hematopoietic tissues. They are non selective cation channels implicated in Ca(2+) signaling in hematologic tumor cells. Here, we review the growing experimental evidence indicating that TRP channels should be included among the genes whose expression is altered in hematologic malignancies such as leukemias (AML, ALL, CML and CLL), B- and T-lymphomas and multiple myelomas (MM). These effects depend on the widespread roles played by the TRP channels in the modulation of the proliferation, differentiation and apoptosis of the hematopoietic cells. The analysis of the expression of the different TRP channels belonging to the TRPMs, TRPVs, TRPCs, TRPPs channel families expressed in different hematological malignacies, evidenced a widespread expression of TRPV2 channel in the myeloid and lymphoid leukemias, and a very peculiar expression of this channel in different types of B cell lymphomas and multiple myeloma, that is parallel to the restricted expression of TRPV2 in normal immune cells with respect to its presence in other human tissues. In vivo studies in children AML and ALL patients also evidenced the presence of a genetic polymorphism of the TRPM5 gene, that reduced the risk to develop leukemia in the children. Finally, the coexpression of TRPV5 and TRPV6 channels in lymphocytes, and their involvement in the radioresistance of K562 erythroleukemia cells to ionizing radiation exposure is of more interest. Thus in conclusion, the TRP channels represent promising targets for hematologic cancer therapy, and their exploitation may open to novel pharmaceutical and clinical approaches.

The role of transient receptor potential vanilloid type-2 ion channels in innate and adaptive immune responses.

The transient receptor potential vanilloid type-2 (TRPV2), belonging to the transient receptor potential channel family, is a specialized ion channel expressed in human and other mammalian immune cells. This channel has been found to be expressed in CD34(+) hematopoietic stem cells, where its cytosolic Ca(2) (+) activity is crucial for stem/progenitor cell cycle progression, growth, and differentiation. In innate immune cells, TRPV2 is expressed in granulocytes, macrophages, and monocytes where it stimulates fMet-Leu-Phe migration, zymosan-, immunoglobulin G-, and complement-mediated phagocytosis, and lipopolysaccharide-induced tumor necrosis factor-alpha and interleukin-6 production. In mast cells, activation of TRPV2 allows intracellular Ca(2) (+) ions flux, thus stimulating protein kinase A-dependent degranulation. In addition, TRPV2 is highly expressed in CD56(+) natural killer cells. TRPV2 orchestrates Ca(2) (+) signal in T cell activation, proliferation, and effector functions. Moreover, messenger RNA for TRPV2 are expressed in CD4(+) and CD8(+) T lymphocytes. Finally, TRPV2 is expressed in CD19(+) B lymphocytes where it regulates Ca(2) (+) release during B cell development and activation. Overall, the specific expression of TRPV2 in immune cells suggests a role in immune-mediated diseases and offers new potential targets for immunomodulation.