Crossing paths in Human Renal Cell Carcinoma (hRCC).

Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.

State of the art in silico tools for the study of signaling pathways in cancer.

In the last several years, researchers have exhibited an intense interest in the evolutionarily conserved signaling pathways that have crucial roles during embryonic development. Interestingly, the malfunctioning of these signaling pathways leads to several human diseases, including cancer. The chemical and biophysical events that occur during cellular signaling, as well as the number of interactions within a signaling pathway, make these systems complex to study. In silico resources are tools used to aid the understanding of cellular signaling pathways. Systems approaches have provided a deeper knowledge of diverse biochemical processes, including individual metabolic pathways, signaling networks and genome-scale metabolic networks. In the future, these tools will be enormously valuable, if they continue to be developed in parallel with growing biological knowledge. In this study, an overview of the bioinformatics resources that are currently available for the analysis of biological networks is provided.

Vinflunine: a new vision that may translate into antiangiogenic and antimetastatic activity.

Microtubules and tubulin are major dynamic and structural cellular components that play a key role in several cell functions, including division, signalling and intracellular trafficking. Normal epithelial cells have a highly structured, rigid cytoskeletal network that is compatible with cell motility. Thus, tubulin and microtubules are compelling cellular targets for chemotherapy. In fact, among anticancer agents, those that target microtubules constitute one of the most effective classes of chemotherapeutics in cancer. The list of compounds that target either tubulin or microtubules is extensive and consists of chemically unique compounds that bind to the tubulin dimers and destabilize microtubules (Vinca alkaloids) and those that bind to the microtubule polymer and stabilize microtubules (taxanes). Tumour-induced angiogenesis, the formation of new capillaries from existing blood vessels, and epithelial-mesenchymal transition are two steps that are critical for both tumour growth and metastatic spread. Three possible mechanisms of action are described with vinflunine, the new-generation Vinca alkaloid to arrive in clinical practice are as follows: it acts against tubulin and microtubules, disrupts newly formed blood vessels and seems to be able to reduce the metastatic process as shown in preclinical studies. These findings support the hypothesis that vinflunine, by blocking microtubule functions that contribute to cell shape, polarization, migration and other processes, might be responsible not only for tumour-cytostatic but also for specific antiangiogenic or antiepithelial-mesenchymal transition effects.

Sunitinib-induced asthenia: from molecular basis to clinical relief.

Asthenia-fatigue syndrome (AFS) is defined as a persistent, subjective sense of tiredness related to cancer or its treatment and greatly impacts quality of life among cancer patients. All tyrosine kinase inhibitors, but especially sunitinib, may induce AFS. The reason for sunitinib-induced AFS is not yet well understood. Adverse events caused by sunitinib associated with AFS may include anemia, hypothyroidism, nausea and vomiting. However, AFS is also reported when active treatment with sunitinib is ongoing, and no other relevant adverse event can justify it. The molecular mechanisms by which sunitinib triggers AFS remain elusive. Sunitinib displays multiple off-target tyrosine-kinase interactions and competitively inhibits multiple proteins through the blockade of their ATP-binding sites. The broad spectrum of kinases inhibited may play a key role not only in terms of activity but also in terms of toxicity induced by sunitinib. This study considered different clinical observations and current metabolic and pharmacological knowledge, leading to hypotheses regarding which molecular mechanisms may be involved in sunitinib-induced AFS in cancer patients. Deeper knowledge of the molecular mode of action of sunitinib may lead to improved optimization of its clinical use.