Extracellular Vesicles in Colorectal Cancer: From Tumor Growth and Metastasis to Biomarkers and Nanomedications.

Colorectal cancer (CRC) is a leading public health concern due to its incidence and high mortality rates, highlighting the requirement of an early diagnosis. Evaluation of circulating extracellular vesicles (EVs) might constitute a noninvasive and reliable approach for CRC detection and for patient follow-up because EVs display the molecular features of the cells they originate. EVs are released by almost all cell types and are mainly categorized as exosomes originating from exocytosis of intraluminal vesicles from multivesicular bodies, ectosomes resulting from outward budding of the plasma membrane and apoptotic bodies' ensuing cell shrinkage.

A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer.

Scaffolding molecules exert a critical role in orchestrating cellular response through the spatiotemporal assembly of effector proteins as signalosomes. By increasing the efficiency and selectivity of intracellular signaling, these molecules can exert (anti/pro)oncogenic activities. As an archetype of scaffolding proteins with tumor suppressor property, the present review focuses on MAGI1, 2, and 3 (membrane-associated guanylate kinase inverted), a subgroup of the MAGUK protein family, that mediate networks involving receptors, junctional complexes, signaling molecules, and the cytoskeleton.

Rac1 Signaling: From Intestinal Homeostasis to Colorectal Cancer Metastasis.

The small GTPase Rac1 has been implicated in a variety of dynamic cell biological processes, including cell proliferation, cell survival, cell-cell contacts, epithelial mesenchymal transition (EMT), cell motility, and invasiveness. These processes are orchestrated through the fine tuning of Rac1 activity by upstream cell surface receptors and effectors that regulate the cycling Rac1-GDP (off state)/Rac1-GTP (on state), but also through the tuning of Rac1 accumulation, activity, and subcellular localization by post translational modifications or recruitment into molecular scaffolds. Another level of regulation involves Rac1 transcripts stability and splicing.

Posttranslational Regulation and Conformational Plasticity of PTEN.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that is frequently down-modulated in human cancer. PTEN inhibits the phosphatidylinositol 3-phosphate kinase (PI3K)/AKT pathway through its lipid phosphatase activity. Multiple PI3K/AKT-independent actions of PTEN, protein-phosphatase activities and functions within the nucleus have also been described.

Targeting PTEN in Colorectal Cancers.

Phosphatase and tensin homolog (PTEN) is a tumour suppressor that represents one of the most common targets for genetic defect in human cancer. PTEN controls an array of physiopathological processes related to cell proliferation, differentiation, DNA/chromosome integrity, apoptosis and invasiveness. PTEN dephosphorylates not only proteins, but also phosphoinositides generated by phosphatidylinositol 3-kinase, thus counteracting the Akt signalling pathway.

Interest of cytology combined with Xpert HPV and Anyplex II HPV28 Detection human papillomavirus (HPV) typing: differential profiles of anal and cervical HPV lesions in HIV-infected patients on antiretroviral therapy.

Objectives: The aim of the study was to assess the interest to combine cytological examination and human papillomavirus (HPV) typing of anal and cervical Papanicolaou (Pap) smears of HIV-infected patients on combination antiretroviral therapy (cART), to evaluate whether differences in prevalence exist between anal and cervical squamous intraepithelial lesions in patients with high-risk oncogenic HPV infection.

Methods: Anal and/or cervical Pap smears were obtained by anoscopy and/or colposcopy in 238 subjects recruited consecutively in 2015: anal smears were obtained from 48 male and female patients [42 men; 35 men who have sex with men (MSM)] and cervical smears from 190 female patients. Cytological Bethesda classification was coupled with HPV typing.

The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression.

We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo.

A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer.

Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer.

Decreased vasorelaxation induced by iloprost during acute inflammation in human internal mammary artery.

Cyclooxygenase-2 (COX-2) induction in human internal mammary arteries (IMA) under inflammatory conditions has been associated with attenuated norepinephrine (NE)-induced vasoconstriction. This effect was associated with increased prostaglandin (PG) E and prostacyclin (PGI) releases. The present study was designed to assess the role of these PG and their receptors (EP and IP, respectively) on the vascular reactivity during acute inflammation.

Nanotechnologies for the treatment of colon cancer: From old drugs to new hope.

Colorectal cancer is a wide-reaching health problem due to its incidence and to the high mortality rates. Adjuvant chemotherapies have considerably improved the prognosis and/or the overall survival of patients with locally advanced and metastatic cancers. Nevertheless, their efficiency remains limited due to intrinsic and emerging multidrug resistance (MDR) of cancer cells, and to major adverse effects and dose limiting toxicities.

Evidence for different expression profiles for c-Met, EGFR, PTEN and the mTOR pathway in low and high grade endometrial carcinomas in a cohort of consecutive women. Occurrence of PIK3CA and K-Ras mutations and microsatellite instability.

Molecular and genetic investigations in endometrial carcinogenesis may have prognostic and therapeutic implications. We studied the expression of EGFR, c-Met, PTEN and the mTOR signalling pathway (phospho-AKT/phospho-mTOR/phospho-RPS6) in 69 consecutive tumours and 16 tissue microarrays. We also analysed PIK3CA, K-Ras mutations and microsatellite instability (MSI).

Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b.

The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Here, we provide evidence for increased expression of Rac1b in patients with inflamed human colonic mucosa as well as following experimentally induced colitis in mice.

Prostaglandin E₂ induced contraction of human intercostal arteries is mediated by the EP₃ receptor.

Arterial vascularization of the spinal cord may be mechanically or functionally altered during thoraco-abdominal surgery/intravascular procedures. Increased arterial pressure has been shown to restore spinal perfusion and function probably by increasing the blood flow through the intercostal arteries. The regulation of human intercostal artery (HICA) vascular tone is not well documented.

Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins.

The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome 10) regulates major cellular functions via lipid phosphatase-dependent and -independent mechanisms. Despite its fundamental pathophysiological importance, how PTEN's cellular activity is regulated has only been partially elucidated. We report that the scaffolding proteins β-arrestins (β-arrs) are important regulators of PTEN.

Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large.

Human disc-large homolog (hDlg), also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. In human vascular tissues, hDlg is highly expressed in smooth muscle cells (VSMCs). Using the yeast two-hybrid system to screen a human aorta cDNA library, we identified mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK)2, a member of the ERK cascade, as an hDlg binding partner.

Differential reactivity of human mammary artery and saphenous vein to prostaglandin E(2) : implication for cardiovascular grafts.

Background And Purpose: Human internal mammary arteries (IMA) and saphenous veins (SV) are frequently used for coronary artery bypass graft surgery. Intra- and postoperatively, the bypass grafts are exposed to inflammatory conditions, under which there is a striking increase in the synthesis of prostaglandin E(2) (PGE(2) ). In this context, the physiological response of these vascular grafts to PGE(2) is highly relevant.

TRIP6, a novel molecular partner of the MAGI-1 scaffolding molecule, promotes invasiveness.

We recently established the critical role of the PTEN/MAGI-1b signalosome in stabilization of cell-cell contacts and suppression of invasiveness. The PTEN tumor suppressor is recruited to E-cadherin junctional complexes through the binding to the second PDZ domain of the MAGI-1b scaffolding molecule, whereas beta-catenin interacts with the fifth PDZ domain. To identify additional effectors of this signalosome, we used yeast 2-hybrid screening.

Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: role of the EP4 receptor subtype.

Background And Purpose: PGE2 has been shown to induce relaxations in precontracted human pulmonary venous preparations, while in pulmonary arteries this response was not observed. We investigated and characterized the prostanoid receptors which are activated by PGE2 in the human pulmonary veins.

Experimental Approach: Human pulmonary arteries and veins were cut as rings and set up in organ baths in presence of a TP antagonist.

Resistin-like molecule beta regulates intestinal mucous secretion and curtails TNBS-induced colitis in mice.

Background: Resistin and resistin-like molecule (RELM)beta comprise a novel class of cysteine-rich proteins secreted into the circulation implicated in hepatic insulin resistance and inflammation. RELMbeta is specifically produced by intestinal goblet cells but regulation of its expression and much of its local function are not elucidated. RELMbeta has been suggested to regulate colonic inflammation susceptibility, which is dependent on the mucosal barrier integrity.

Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis.

Imbalance of signals that control cell survival and death results in pathologies, including cancer and neurodegeneration. Two pathways that are integral to setting the balance between cell survival and cell death are controlled by lipid-activated protein kinase B (PKB)/Akt and Ca(2+). PKB elicits its effects through the phosphorylation and inactivation of proapoptotic factors.

A new mRNA splice variant coding for the human EP3-I receptor isoform.

The cellular localization of prostaglandin E2 receptors (EP) and their corresponding transcripts were investigated in human gastric and vascular tissues. A strong staining of the EP3 receptor on the gastric glands, mucous cells, media of the mammary and pulmonary arteries was observed by immunohistochemistry. We identified a new mRNA splice variant of the EP3 gene in human gastric fundic mucosa, mammary artery and pulmonary vessels.

Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2.

The recently identified subfamily of WNK protein kinases is characterized by a unique sequence variation in the catalytic domain and four related human WNK genes were identified. Here, we describe the cloning and functional analysis of the human family member WNK2. We show that the depletion of endogenous WNK2 expression by RNA interference in human cervical HeLa cancer cells led to the activation of the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases but, in contrast to the depletion of WNK1, had no effect on ERK5.

Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells.

The search for effective chemopreventive compounds is a major challenge facing research into preventing the progression of cancer cells. The naturally occurring polyphenol antioxidants look very promising, but their mechanism of action still remains poorly understood. Here, we show that 2-(3,4-dihydroxyphenyl)ethanol (DPE), a phenol antioxidant derived from olive oil, induces growth arrest and apoptosis in human colon carcinoma HT-29 cells.

Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc(Min/+) mice.

Background And Aims: Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc(Min/+) mice.

Cholinesterase activity in human pulmonary arteries and veins: correlation with mRNA levels.

Isolated intact human pulmonary arteries and veins were used to determine the acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) activities in the absence or presence of two selective cholinesterase (ChE) inhibitors, iso-OMPA or BW284c51, respectively. These results were compared with the mRNA levels for each enzyme in human pulmonary vessels. Total ChE activities measured in presence of acetylthiocholine (ACTI, 1 mM) in intact vascular preparations were 45+/-04 and 114+/-07 mU/g tissue in human pulmonary arteries (n=14) and veins (n=14), respectively.