Carcinogenesis and Metastasis: Focus on TRPV1-Positive Neurons and Immune Cells.

Both sensory neurons and immune cells, albeit at markedly different levels, express the vanilloid (capsaicin) receptor, Transient Receptor Potential, Vanilloid-1 (TRPV1). Activation of TRPV1 channels in sensory afferent nerve fibers induces local effector functions by releasing neuropeptides (most notably, substance P) which, in turn, trigger neurogenic inflammation. There is good evidence that chronic activation or inactivation of this inflammatory pathway can modify tumor growth and metastasis. TRPV1 expression was also demonstrated in a variety of mammalian immune cells, including lymphocytes, dendritic cells, macrophages and neutrophils. Therefore, the effects of TRPV1 agonists and antagonists may vary depending on the prominent cell type(s) activated and/or inhibited. Therefore, a comprehensive understanding of TRPV1 activity on immune cells and nerve endings in distinct locations is necessary to predict the outcome of therapies targeting TRPV1 channels. Here, we review the neuro-immune modulation of cancer growth and metastasis, with focus on the consequences of TRPV1 activation in nerve fibers and immune cells. Lastly, the potential use of TRPV1 modulators in cancer therapy is discussed.

"ThermoTRP" Channel Expression in Cancers: Implications for Diagnosis and Prognosis (Practical Approach by a Pathologist).

Temperature-sensitive transient receptor potential (TRP) channels (so-called "thermoTRPs") are multifunctional signaling molecules with important roles in cell growth and differentiation. Several "thermoTRP" channels show altered expression in cancers, though it is unclear if this is a cause or consequence of the disease. Regardless of the underlying pathology, this altered expression may potentially be used for cancer diagnosis and prognostication. "ThermoTRP" expression may distinguish between benign and malignant lesions. For example, TRPV1 is expressed in benign gastric mucosa, but is absent in gastric adenocarcinoma. TRPV1 is also expressed both in normal urothelia and non-invasive papillary urothelial carcinoma, but no TRPV1 expression has been seen in invasive urothelial carcinoma. "ThermoTRP" expression can also be used to predict clinical outcomes. For instance, in prostate cancer, TRPM8 expression predicts aggressive behavior with early metastatic disease. Furthermore, TRPV1 expression can dissect a subset of pulmonary adenocarcinoma patients with bad prognosis and resistance to a number of commonly used chemotherapeutic agents. This review will explore the current state of this rapidly evolving field with special emphasis on immunostains that can already be added to the armoire of diagnostic pathologists.

The antimalarial artemisinin is a non-electrophilic agonist of the transient receptor potential ankyrin type 1 receptor-channel.

Artemisinin and its derivatives are the main therapeutic drugs against Plasmodium protists, the causative agents of malaria. While several putative mechanisms of action have been proposed, the precise molecular targets of these compounds have not been fully elucidated. In addition to their antimalarial properties, artemisinins have been reported to act as anti-tumour agents and certain antinociceptive effects have also been proposed. We investigated the effect of the parent compound, artemisinin, on a number of temperature-gated Transient Receptor Potential ion channels (so called thermoTRPs), given their demonstrated roles in pain-sensing and cancer. We report that artemisinin acts as an agonist of the Transient Receptor Potential Ankyrin type 1 (TRPA1) receptor channel. Artemisinin was able to evoke calcium transients in HEK293T cells expressing recombinant human TRPA1, as well as in a subpopulation of mouse dorsal root ganglion (DRG) neurons which also responded to the selective TRPA1 agonist allyl isothiocyanate (AITC) and these responses were reversibly abolished by the selective TRPA1 antagonist A967079. Artemisinin also triggered whole-cell currents in HEK293T cells transiently transfected with human TRPA1, as well as in TRPA1-expressing DRG neurons, and these currents were inhibited by A967079. Interestingly, using human TRPA1 mutants, we demonstrate that artemisinin acts as a non-electrophilic agonist of TRPA1, activating the channel in a similar manner to carvacrol and menthol. These results may provide a better understanding of the biological actions of the very important antimalarial and anti-tumour agent artemisinin.

Paclitaxel in vitro reversibly sensitizes the excitability of IB4(-) and IB4(+) sensory neurons from male and female rats.

BACKGROUND AND PURPOSE: Paclitaxel produces a chemotherapy-induced peripheral neuropathy that persists in 50-60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A- and C-type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood. EXPERIMENTAL APPROACH: We used a long-lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4(-) and IB4(+) sensory neurons of female and male adult Wistar rats. KEY RESULTS: Paclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4(-) and IB4(+) neurons in both sexes, peaking at 48 h post-treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after-hyperpolarization phase. Molecularly, paclitaxel modulated Na+ and K+ ion currents. Particularly, the drug significantly augmented the function of Nav 1.8, TRPV1 and TRPM8 channels. Furthermore, paclitaxel increased Nav 1.8 and TRPV1 expression at 48 h post-treatment. Notably, we observed that female DRG neurons appear more sensitive to paclitaxel sensitization than their male counterparts. CONCLUSIONS AND IMPLICATIONS: Our data indicate that paclitaxel similarly potentiated IB4(-) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel-induced chemotherapy-induced peripheral neuropathy. Our in vitro, pre-clinical, chemotherapy-induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.

Calcium Entry Through Thermosensory Channels.

ThermoTRPs are unique channels that mediate Na(+) and Ca(2+) currents in response to changes in ambient temperature. In combination with their activation by other physical and chemical stimuli, they are considered key integrators of environmental cues into neuronal excitability. Furthermore, roles of thermoTRPs in non-neuronal tissues are currently emerging such as insulin secretion in pancreatic ß-cells, and links to cancer. Calcium permeability through thermoTRPs appears a central hallmark for their physiological and pathological activities. Moreover, it is currently being proposed that beyond working as a second messenger, Ca(2+) can function locally by acting on protein complexes near the membrane. Interestingly, thermoTRPs can enhance and expand the inherent plasticity of signalplexes by conferring them temperature, pH and lipid regulation through Ca(2+) signalling. Thus, unveiling the local role of Ca(2+) fluxes induced by thermoTRPs on the dynamics of membrane-attached signalling complexes as well as their significance in cellular processes, are central issues that will expand the opportunities for therapeutic intervention in disorders involving dysfunction of thermoTRP channels.

Targeting TRP channels for pain relief.

Preclinical research has recently uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent opportunities for pharmacological intervention. Manipulating temperature-sensitive Transient Receptor Potential (TRP) channels (so-called "thermoTRPs") on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. In the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels. TRPV1 desensitization by topical agonists (e.g. high concentration capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific resiniferatoxin (an ultrapotent capsaicin analogue) injections are being evaluated as "molecular scalpels" to achieve permanent analgesia in cancer patients with chronic, intractable pain. In the past few years a number of potent, small molecule TRPV1, TRPV3 and TRPA1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. TRPM8 antagonists are following closely behind for cold allodynia. Early TRPV1 antagonists in the clinic, however, showed worrisome adverse effects including hyperthermia and impaired noxious heat sensation. These adverse effects placed the patients at risk for scalding injury and prompted their withdrawal from the clinical trials. Second generation TRPV1 antagonists that do not cause core body temperature elevation have been reported, although the therapeutic utility of this class of compounds is not yet known. This review discusses the promise and challenges of developing TRP channel antagonists as a new generation of pain therapeutics.