Immune-modulating nanomedicines for enhanced drug delivery to non-small-cell lung cancer.

Immune-modulating peptides have shown potential as novel immune-stimulating agents which enhance the secretion of anticancer cytokines in vitro. However, fast clearance from blood hampers the ability of such peptides to accumulate in the tumour and results in limited therapeutic efficacy in animal studies. To address the fast blood clearance, this work reports the development and validation of a novel polymeric nanoparticle delivery system for the efficient localization of an immunomodulating peptide in the tumour microenvironment (TME).

An immunomodulating peptide to counteract solar radiation-induced immunosuppression and DNA damage.

Ultraviolet radiation (UVR) induces immunosuppression and DNA damage, both of which contribute to the rising global incidence of skin cancer including melanoma. Nucleotide excision repair, which is activated upon UVR-induced DNA damage, is linked to expression of interleukin-12 (IL-12) which serves to limit immunosuppression and augment the DNA repair process. Herein, we report an immunomodulating peptide, designated IK14800, that not only elicits secretion of IL-12, interleukin-2 (IL-2) and interferon-gamma (IFN-γ) but also reduces DNA damage in the skin following exposure to UVR.

A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses.

T cell-dendritic cell (DC) interactions contribute to reciprocal stimulation leading to DC maturation that results in production of interleukin-12 (IL-12) and interferon-gamma (IFN-γ). Both cytokines have been implicated in autoimmune diseases while being necessary for effective immune responses against foreign antigens. We describe a lipidic peptide, designated IK14004, that modifies crosstalk between T cells and DCs resulting in suppression of IL-12p40/IFN-γ production.

Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts.

Tumor microenvironment (TME) is the cellular environment in which tumor exists, and it contributes to tumor formation and progression. The TME is composed of tumor cells, stromal cells, cytokines, and chemotactic factors of which fibroblasts are the main cellular components. In our present study, we found that colorectal cancer (CRC) cells expressing integrin αvβ6 clearly could induce morphological changes in inactive fibroblasts and increased the expression of activated fibroblast markers such as α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP).

Norcantharidin Suppresses Colon Cancer Cell Epithelial-Mesenchymal Transition by Inhibiting the αvβ6-ERK-Ets1 Signaling Pathway.

Norcantharidin (NCTD) is an efficacious anti-cancer drug that has been used in China for many years, but its underlying mechanism of action is still not fully understood. In the present study, we found that NCTD could induce morphological changes in colon cancer cells, causing a transition from a spindle-shaped morphology to a typical round or oval shape, which was indicative of a mesenchymal-epithelial transition (MET) process. Next, we investigated the mechanism by which NCTD induced the MET process.

Characterization of the interaction between heterodimeric αvβ6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics.

Urokinase plasminogen activator receptor (uPAR) and the epithelial integrin αvβ6 are thought to individually play critical roles in cancer metastasis. These observations have been highlighted by the recent discovery (by proteomics) of an interaction between these two molecules, which are also both implicated in the epithelial-mesenchymal transition (EMT) that facilitates escape of cells from tissue barriers and is a common signature of cancer metastases. In this study, orthogonal in cellulo and in vitro functional proteomic approaches were used to better characterize the uPAR·αvβ6 interaction.

Integrin αvβ6 and transcriptional factor Ets-1 act as prognostic indicators in colorectal cancer.

Background: Both transcriptional factor Ets-1 and integrin αvβ6 play an important role in the development and progression of cancer. The aim of our study was to investigate the expression of Integrin αvβ6 and Ets-1, two proteins' correlation and their clinical significance in colorectal cancerous tissues.

Results: The specimens were arranged into microarray using the immunohistochemistry method to investigate the expression of integrin αvβ6 and transcriptional factor Ets-1 in these tissues.

PKC promotes the migration of colon cancer cells by regulating the internalization and recycling of integrin αvβ6.

Recently published studies have suggested that integrin trafficking is necessary to support cell migration, but the role of internalization and recycling of integrin αvβ6 in colon cancer cells remained unclear. In our study, we demonstrated the existence of the integrin cycle and found that inhibition of ERK2 phosphorylation by PD98059 or deletion of the ERK2 direct binding site on the β6 cytoplasmic domain could interrupt the internalization of integrin αvβ6, but had no effect on its recycling. Furthermore, integrin αvβ6 trafficking played a key role in the migration of colon cancer cells towards fibronectin.

Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6-extracellular signal-related kinase signaling pathway.

Norcantharidin has been used as an efficacious anticancer drug in China for many years, but its true mechanism remains poorly understood. Intriguingly, in an in vitro series study of anticancer drugs, we found that norcantharidin can effectively inhibit epithelial tumor cells from expressing integrin alphavbeta6. Our previous studies have confirmed that integrin alphavbeta6 is closely relevant to malignant epithelial cell tumor biology behavior, and it can promote cancer cells to invade and metastasize through a special alphavbeta6-extracellular signal-related kinase (ERK) direct signaling pathway.

Suppression of integrin alphaupsilonbeta6 by RNA interference in colon cancer cells inhibits extracellular matrix degradation through the MAPK pathway.

Integrin alphaupsilonbeta6 plays a very important role in the progression of colon cancer cells and is now defined as a novel, independent prognostic indicator for aggressive colon cancer in humans. Herein, we use the RNA interfering technology to downregulate the expression of alphaupsilonbeta6 in colon cancer cells. Our data demonstrate that plasmid vector based shRNA can effectively down-regulate alphaupsilonbeta6 expression in protein and mRNA levels.

alpha(v)beta(6) Integrin expression in diseased and transplanted kidneys.

Background: Integrins have been implicated in the pathogenesis of a diverse range of kidney diseases. Herein, we provide the first detailed description of an epithelial restricted integrin, alpha(v)beta(6), in kidney biopsies from patients suffering acute and chronic renal diseases and after transplantation.

Methods: Immunoperoxidase staining for beta(6) was performed on 267 selected biopsy specimens from native (N= 126) and transplanted kidneys (N= 141) and scored semiquantitatively.

Rectal cancer masquerading as an amoeboma: case report and review of the literature.

Despite the prevalence of amoebiasis in many parts of the world, amoebomas are relatively uncommon. Amoebomas within the colorectum are indistinguishable from carcinomas either macroscopically or by barium enema examination and the presence of both conditions is much rarer still. Herein, we describe such a case and review the possible reasons for their coexistence.

Trialling a new way to learn clinical skills: systematic clinical appraisal and learning.

Aim: To describe and evaluate the effectiveness of a new method of teaching clinical skills designed to increase students' active and self-directed learning as well as tutor feedback.

Methods: A total of 22 consenting Year 4 medical students undertaking general practice and general surgery clinical experience were involved in a pre- and post-test research design. In the initial period of the study, students were taught clinical skills in a traditional manner.

Integrin alpha(v)beta6-associated ERK2 mediates MMP-9 secretion in colon cancer cells.

There is general consensus that matrix metalloproteinases are involved in tumour progression. We show herein that inhibition of integrin alpha(v)beta6 expression in colon cancer cells suppresses MMP-9 secretion. This integrin-mediated event is dependent upon direct binding between the beta6 integrin subunit and extracellular signal-regulated kinase 2.

Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the beta6 integrin subunit.

We have previously reported that the alphavbeta6 integrin upregulates its own expression in a protein kinase C-dependent manner with increasing cell density. The wild-type beta6 integrin subunit has also been shown to promote tumour growth in vivo and its growth-enhancing effect is regulated by both a MAP kinase binding motif on beta6 and the 11 amino acid C-terminal cytoplasmic extension unique to the beta6 subunit. Herein, we show that the 11 amino acid cytoplasmic extension is essential for the cell density-dependent increase in beta6 expression and that the 11 amino acid tail exerts a dominant negative effect on cell density- and PKC-mediated beta5 expression in alphavbeta6-expressing colon cancer cells.

Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade.

Recent evidence suggests that integrins are involved in the multi-step process of tumour metastasis. The biological relevance of alpha(v) integrins and associated beta-subunits in ovarian cancer metastasis was examined by analysing the expression of these cell surface receptors in nine ovarian cancer cell lines and also in the primary human ovarian surface epithelial cell line (HOSE). beta1, beta3 and beta5 subunits were present in all ten ovarian cell lines.

Direct integrin alphavbeta6-ERK binding: implications for tumour growth.

Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth of colon cancer in vivo. Here we demonstrate a direct link between the extracellular signal-regulated kinase ERK2 and the growth-promoting cell adhesion molecule, integrin alphavbeta6, in colon cancer cells. Down-regulation of beta6 integrin subunit expression inhibits tumour growth in vivo and MAP kinase activity in response to serum stimulation.

The alphaVbeta6 integrin regulates its own expression with cell crowding: implications for tumour progression.

Expression of the growth-promoting integrin alphavbeta6 in colon cancer cells induces gelatinase B secretion and activation, the inhibition of which abolishes alphavbeta6-mediated tumour cell growth within a collagen matrix. Herein, we show that high cell density selectively enhances alphavbeta6 expression in a protein kinase C (PKC)-dependent manner in preference to other beta integrin subunits, resulting in a marked increase in gelatinase B secretion as cells reach confluence. Moreover, PKC activity increases with cell confluence, and the rise in PKC activity is much greater for alphavbeta6-expressing cells than for colon cancer cells which lack alphavbeta6.

Matrix metalloproteinase 9 activity in urine of patients at risk for premature delivery.

A simple, noninvasive assay was used to quantitate urinary matrix metalloproteinase 9 activity among 15 patients with threatened premature labor. Both positive and negative predictive values for risk for premature delivery were 80%.

The alpha v beta 6 integrin induces gelatinase B secretion in colon cancer cells.

In human cancers, the co-operative role between cell-adhesion receptors and proteases capable of degrading matrix barriers remains poorly understood. We have previously reported that the epithelium-restricted integrin alpha(v)beta6 becomes highly expressed in colon cancer compared with normal mucosa and that heterologous expression of alpha(v)beta6 in colon cancer cells is associated with enhanced cell growth. Herein, we report that alpha(v)beta6 expression in colon cancer cells leads to a relative increase in secretion of the matrix metalloproteinase gelatinase B over its respective inhibitor and that this secretion parallels the level of cell-surface beta6 expression.