Extracellular acidity as favouring factor of tumor progression and metastatic dissemination

The bidirectional interactions between tumor cells and the so-called “host reactive stroma” play a critical role in most of the events characterizing tumor progression and distant organ colonization. This review discusses critical components of tumor environment involved in tumor cell dissemination. More specifically, it addresses some of the experimental evidences providing that acidity of tumor environment facilitates local invasiveness and metastasis formation, independently from hypoxia, with which acidity may be associated. Besides, acidity renders tumor cells resistant to radiation therapy and chemotherapeutic drugs. Therefore, this review examines the strategies for raising the low extracellular pH of tumors that might have considerable potential in cancer therapy

A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer

The emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 affects cell viability and colony forming capability to greater extent than either treatment alone of breast, colorectal and melanoma cancer cells. At the molecular level, this therapeutic regimen resulted in a synergistically increase of histone H4 and p53 acetylation in all tested cell lines. Overall, our findings showed that SAHA and SLC-0111 can be regarded as very attractive combination providing a potential therapeutic strategy against different cancer models

uPAR controls vasculogenic mimicry ability expressed by drug-resistant melanoma cells.

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAF(V600E) inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenib-resistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease

A Fluorescent Glycolipid-Binding Peptide Probe Traces Cholesterol Dependent Microdomain-Derived Trafficking Pathways

10.1371/journal.pone.0002933PLoS ONE38

TNFα receptor1 drives hypoxia-promoted invasiveness of human melanoma cells

Aim: Oxygen deprivation leading to hypoxia represents a common feature of advanced solid tumors, able to control several aspects of tumor progression. Indeed, ability to respond to changes in oxygen partial pressure represents a hallmark of malignant cells. Aim of this study is to disclose new pathway of hypoxia-induced tumor cell invasion. Materials and Methods: Hs294T human melanoma cells were grown in a gas mixture containing 0.3 % , and used to evaluate invasion on Matrigel-coated polycarbonate filters mounted in Boyden's chambers, MMP release and expression of inflammatory receptors and their ligands. Results: We demonstrate that hypoxia promotes the expression of TNFa receptor 1 (TNFαR1) able to drive a higher ability to penetrate Matrigel-coated filters of Hs294T human melanoma cells, an effect does not mediated by hypoxia-inducible factor (HIF)-1α. Conclusion: Expression inflammatory cytokine receptors in hypoxic human melanoma cells might provide a new target for improving strategies against local and distant tumor cell diffusion. Key Words: TNFa receptor 1, Hs294T human melanoma cells, hypoxia, cell invasiveness, metalloproteinase 2 and 9