Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.

The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesicles (EVs), membrane-enclosed structures released into the extracellular milieu by tumor/host cells, are now recognized as critical drivers in the complex intercellular communication between tumor cells and the local cellular components in a hypoxic/acidic microenvironment.

The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs.

Gastric cancer (GC) is the fifth most frequent malignancy and the fourth leading cause of worldwide cancer-related death. Despite the usage of multimodal perioperative chemotherapy (pCT), GC progressively gains chemoresistance, thereby, the identification of suitable targets to overcome drug resistance is fundamental. Amongst the potential biomarkers, carbonic anhydrase IX (CAIX) - associated with a poor prognosis of several solid cancers - has gained the most attention.

Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species.

Blood vessels are the most important way for cancer cells to survive and diffuse in the body, metastasizing distant organs. During the process of tumor expansion, the neoplastic mass progressively induces modifications in the microenvironment due to its uncontrolled growth, generating a hypoxic and low pH milieu with high fluid pressure and low nutrients concentration. In such a particular condition, reactive oxygen species play a fundamental role, enhancing tumor proliferation and migration, inducing a glycolytic phenotype and promoting angiogenesis.

An Oleocanthal-Enriched EVO Oil Extract Induces the ROS Production in Gastric Cancer Cells and Potentiates the Effect of Chemotherapy.

Oleocanthal, a minor polar compound in extra-virgin olive (EVO) oil, contains anticancer properties, which should be encouraged in its use in oncology. Gastric Cancer (GC), a very aggressive human cancer, is often diagnosed at advanced stages, when surgery is substituted or supported by chemotherapy (CT). However, CT frequently fails due to the patient's resistance to the treatment.

Colon fibroblasts from Pirc rats (F344/NTac-Apc ) exhibit a proliferative and inflammatory phenotype that could support early stages of colon carcinogenesis.

The role of fibroblast APC mutation in carcinogenesis is not clear. Apc colon fibroblasts have been previously characterized: however, little is known about their behavior at very early-stage of colon carcinogenesis. We cultured colon mucosa fibroblasts (PCF, Apc ) of Pirc rats (F344/NTac-Apc ) at an early stage of tumorigenesis, in absence of preneoplastic lesions, and of age-matched wt (WCF): DNA damage levels, inflammatory phenotype and the expression of known markers of CAFs were analyzed.

Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line.

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure.

Small nucleolar RNA host genes promoting epithelial-mesenchymal transition lead cancer progression and metastasis.

The small nucleolar RNA host genes (SNHGs) belong to the long non-coding RNAs and are reported to be able to influence all three levels of cellular information-bearing molecules, that is, DNA, RNA, and proteins, resulting in the generation of complex phenomena. As the host genes of the small nucleolar RNAs (snoRNAs), they are commonly localized in the nucleolus, where they exert multiple regulatory functions orchestrating cellular homeostasis and differentiation as well as metastasis and chemoresistance. Indeed, worldwide literature has reported their involvement in the epithelial-mesenchymal transition (EMT) of different histotypes of cancer, being able to exploit peculiar features, for example, the possibility to act both in the nucleus and the cytoplasm.

5-Fluorouracil Conversion Pathway Mutations in Gastric Cancer.

To date, 5-Fluorouracil (5FU) is a major component of several chemotherapy regimens, thus its study is of fundamental importance to better understand all the causes that may lead to chemoresistance and treatment failure. Given the evident differences between prognosis in Asian and Caucasian populations, triggered by clear genetic discordances and given the extreme genetic heterogeneity of gastric cancer (GC), the evaluation of the most frequent mutations in every single member of the 5FU conversion and activation pathway might reveal several important results. Here, we exploited the cBioPortal analysis software to query a large databank of clinical and wide-genome studies to evaluate the components of the three major 5FU transformation pathways.

The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells.

Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both "aerobic" and "anaerobic" glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression.

MAP Kinases Pathways in Gastric Cancer.

Gastric cancer (GC) is turning out today to be one of the most important welfare issues for both Asian and European countries. Indeed, while the vast majority of the disease burden is located in China and in Pacific and East Asia, GC in European countries still account for about 100,000 deaths per year. With this review article, we aim to focus the attention on one of the most complex cellular pathways involved in GC proliferation, invasion, migration, and metastasis: the MAP kinases.

Update on gastric cancer treatments and gene therapies.

Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations.

Stromal-induced mitochondrial re-education: Impact on epithelial-to-mesenchymal transition and cancer aggressiveness.

Metabolic reprogramming as well as the flexible utilisation of fuel sources by tumour cells has been considered not only intrinsic to malignant cells but also sustained by resident and/or recruited stromal cells. The complexity of tumour-stroma cross-talk is experienced by neoplastic cells through profound changes in the own metabolic machinery. In such context, mitochondria are dynamic organelles that receive, orchestrate and exchange a multiplicity of stromal cues within the tumour cells to finely regulate key metabolic and signalling pathways, allowing malignant cells to adapt and thrive in an ever-changing environment.

Serpin A1 and the modulation of type I collagen turnover: Effect of the C-terminal peptide 409-418 (SA1-III) in human dermal fibroblasts.

The pharmacological modulation of collagen turnover is a strategy potentially useful in different skin conditions. The serine protease inhibitor Serpin A1 and portions of its C-terminal region have been investigated as collagen modulators. To clarify the mechanisms by which the C-terminal 409-418 peptide SA1-III increases extracellular type I collagen levels, to compare its activities range with that of the originator molecule Serpin A1, and to evaluate its efficacy in primary cultures from adult and aged human subjects.

Plasmatic carbonic anhydrase IX as a diagnostic marker for clear cell renal cell carcinoma.

Carbonic anhydrase (CA, EC 4.2.1.

Roles of different IRES-dependent FGF2 isoforms in the acquisition of the major aggressive features of human metastatic melanoma.

Unlabelled: Fibroblast growth factor 2 (FGF2) is involved in many physiological and pathological processes. Fgf2 deregulation contributes to the acquisition of malignant features of melanoma and other cancers. FGF2 is an alternative translation product expressed as five isoforms, a low-molecular-weight (18 KDa) and four high-molecular-weight (22, 22.

Desmoglein-2-integrin Beta-8 interaction regulates actin assembly in endothelial cells: deregulation in systemic sclerosis.

Background: The inability of endothelial cells of patients affected by the diffuse form of Systemic sclerosis (SSc) to perform angiogenesis is a marker of the disease. We previously demonstrated that desmoglein-2 reduction is a major difference between (SSc)-microvascular endothelial cells (MVECs) and normal (N)-MVECs. Here we investigated the role of desmoglein-2 in human N-MVECs and SSc-MVECs angiogenesis.

GDF5 regulates TGFß-dependent angiogenesis in breast carcinoma MCF-7 cells: in vitro and in vivo control by anti-TGFß peptides.

Background: TGFß overproduction in cancer cells is one of the main characteristics of late tumor progression being implicated in metastasis, tumor growth, angiogenesis and immune response. We investigated the therapeutic efficacy of anti-TGFß peptides in the control of angiogenesis elicited by conditional over-expression of TGFß.

Methods: We have inserted in human MCF7 mammary-cancer cells a mutated TGFß gene in a tetracycline-repressible vector to obtain conditional expression of mature TGFß upon transient transfection, evaluated the signaling pathways involved in TGFß-dependent endothelial cells activation and the efficacy of anti-TGFß peptides in the control of MCF7-TGFß-dependent angiogenesis.

Systemic sclerosis endothelial cells recruit and activate dermal fibroblasts by induction of a connective tissue growth factor (CCN2)/transforming growth factor β-dependent mesenchymal-to-mesenchymal transition.

Objective: Clinical evidence suggests that the vascular abnormalities of systemic sclerosis (SSc) precede the onset of fibrosis, but molecular cues accounting for a possible vascular connection of SSc fibrosis have been elusive, although they have been searched for intensively. Since we had previously shown that connective tissue growth factor (CCN2), endowed with fibroblast-oriented activities, was overexpressed by endothelial cells (ECs) from SSc patients, we undertook this study to investigate its role and mechanisms in fibroblast activation.

Methods: Normal fibroblasts were challenged with conditioned medium of normal microvascular ECs (MVECs) and MVECs obtained from SSc patients with the diffuse form of the disease.

Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae.

Endothelial urokinase-type plasminogen activator receptor (uPAR) is thought to provide a regulatory mechanism in angiogenesis. Here we studied the proangiogenic role of uPAR in endothelial colony-forming cells (ECFCs), a cell population identified in human umbilical blood that embodies all of the properties of an endothelial progenitor cell matched with a high proliferative rate. By using caveolae-disrupting agents and by caveolin-1 silencing, we have shown that the angiogenic properties of ECFCs depend on caveolae integrity and on the presence of full-length uPAR in such specialized membrane invaginations.

Low doses of 3-aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, stimulate angiogenesis by regulating expression of urokinase type plasminogen activator and matrix metalloprotease 2.

Background: Poly(ADP-Ribose) polymerase (PARP) activity has been demonstrated fundamental in many cellular processes, including DNA repair, cell proliferation and differentiation. In particular, PARP activity has been recently found to affect proliferation, migration, and tube formation of human umbilical vein endothelial cells. In recent times, PARP inhibitors have entered in clinical trials to potentiate cancer treatments by preventing DNA repair, but little is known about the effects performed by different drug concentrations on neoangiogenesis, an essential step in tumor growth.

Differentiating and apoptotic dose-dependent effects in (-)-alpha-bisabolol-treated human endothelial cells.

The effect on angiogenesis of (-)-alpha-bisabolol [(-)-6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol] (1), a widely distributed plant sesquiterpene alcohol, was investigated for the first time. Human endothelial cells treated with 1 were analyzed for their ability to differentiate and organize in microvessels and for their sensitivity to this compound in terms of cytotoxicity and cell growth inhibition. Within 24 h of the treatment with 5 microM 1, cells underwent massive death.

Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells.

Purpose: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

Experimental Design: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines.

Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells.

Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer.