Fibroblasts in pancreatic cancer: molecular and clinical perspectives

Pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) are highly abundant cells in the pancreatic tumor microenvironment (TME) that modulate desmoplasia. The formation of a dense stroma leads to immunosuppression and therapy resistance that are major causes of treatment failure in pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that several subpopulations of CAFs in the TME can interconvert, explaining the dual roles (antitumorigenic and protumorigenic) of CAFs in PDAC and the contradictory results of CAF-targeted therapies in clinical trials. This highlights the need to clarify CAF heterogeneity and their interactions with PDAC cells. This review focuses on the communication between activated PSCs/CAFs and PDAC cells, as well as on the mechanisms underlying this crosstalk. CAF-focused therapies and emerging biomarkers are also outlined.     

Understanding metabolic alterations in cancer cells: a promising new/old approach to eradicate cancer

Alterations in several aspects of cell metabolism have recently been re-discovered as one of the main features of most cancer cells. The three minireviews discuss how alterations in the glycolytic pathway, in lipid metabolism and in amino acid sensing may give a growth advantage to cells with high proliferative rates, experiencing inadequate nutrients availability.     

Bioinformatics approaches for new drug discovery: a review

Prolonged antibiotic therapy for the bacterial infections has resulted in high levels of antibiotic resistance. Initially, bacteria are susceptible to the antibiotics, but can gradually develop resistance. Treating such drug-resistant bacteria remains difficult or even impossible. Hence, there is a need to develop effective drugs against bacterial pathogens. The drug discovery process is time-consuming, expensive and laborious. The traditionally available drug discovery process initiates with the identification of target as well as the most promising drug molecule, followed by the optimization of this, in-vitro, in-vivo and in pre-clinical studies to decide whether the compound has the potential to be developed as a drug molecule. Drug discovery, drug development and commercialization are complicated processes. To overcome some of these problems, there are many computational tools available for new drug discovery, which could be cost effective and less time-consuming. In-silico approaches can reduce the number of potential compounds from hundreds of thousands to the tens of thousands which could be studied for drug discovery and this results in savings of time, money and human resources. Our review is on the various computational methods employed in new drug discovery processes.     

HMP19 is a new metastasis suppressor in epithelial ovarian cancer

HMP19 is a neuron-specific gene; its expression product belongs to a family of neuronal proteins which can be found in numerous kinds of human cancers. However, the clinicopathological significance of HMP19 expression in epithelial ovarian cancer (EOC) is as yet unknown. In this study, protein expression levels of HMP19 in cancerous tissues were determined by tissue microarray immunohistochemistry analysis (TMA-IHC) (n = 117). HMP19 protein levels in cancer tissues were associated with clinical characteristics and overall survival rates of patients with EOC. It was found that both mRNA and protein levels of HMP19 were significantly lower in EOC than those in normal ovary or fallopian tube tissues (P<0.05). The protein expression level of HMP19 was significantly associated with a lower FIGO stage, a lower level of CA-125 and a lower presence of metastasis. Consistent with related adverse clinical pathological features, the overall survival (OS) rate of patients with low or non HMP19-expressing tumors was inferior compared to those with high HMP19-expressing tumors. This is in accordance with further studies that found high HMP19 protein level to be an independent prognostic factor for OS in EOC. Multivariate analysis demonstrated that tumor patients with low HMP19 expression had an exceedingly poor OS. HMP19 plays a role in metastasis/tumor suppression and offers a prognostic value for EOC. HMP19, as a new inhibitor, strongly inhibits metastasis and partially attenuates tumor growth in EOC.     

Understanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches

Monoclonal antibodies coupled to highly toxic molecules (immunoconjugates) are currently being developed for cancer therapy. We have used an in silico procedure for evaluating some physicochemical properties of two tumor-targeting anti-HER2 immunoconjugates: (a) the single-chain antibody scFv(FRP5) linked to a bacterial toxin, that has been recently progressed to phase I clinical trial in human cancer; (b) the putative molecule formed by the intrinsically stable scFv(800E6), which has been proposed as toxin carrier to cancer cells in human therapy, joined to the same toxin of (a). Structural models of the immunoconjugates have been built by homology modeling and assessed by molecular dynamics simulations. The trajectories have been analyzed to extract some biochemical properties and to assess the potential effects of the toxin on the structure and dynamics of the anti-HER2 antibodies. The results of the computational approach indicate that the antibodies maintain their correct folding even in presence of the toxin, whereas a certain stiffness in correspondence of some structural regions is observed. Furthermore, the toxin does not seem to affect the antibody solubility, whereas it enhances the structural stability. The proposed computational approach represent a promising tool for analyzing some physicochemical properties of immunoconjugates and for predicting the effects of the linked toxin on structure, dynamics, and functionality of the antibodies.     

A call for a new paradigm of island biogeography

MacArthur and Wilson’s equilibrium theory of island biogeography quickly became the paradigm of the field in the 1960s and has strongly influenced this and other disciplines of ecology and conservation biology for the past three decades. Recently, however, a growing number of ecologists have begun to question whether the theory remains a useful paradigm for modern ecology. We now have a much better appreciation for the complexity of nature and we study patterns that span a very broad range in spatial, temporal and ecological scales. At such scales, assumptions that communities are in equilibrium, that species, islands and intervening landscapes or seascapes are equivalent or homogeneous with respect to factors influencing immigration and extinction, and that in situ speciation can be overlooked become very tenuous. With this in mind, this and other papers of this special feature discuss the principal, conceptual shortcomings of the equilibrium theory and offer some modifications or alternatives to the theory that we hope will eventually lead to a more comprehensive understanding of the forces structuring insular communities.     

Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches

The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed.     

CCN1: a novel target for pancreatic cancer

CCN2 (formerly known as connective tissue growth factor) was identified by several different laboratories approximately 20 years ago. Almost since its identification as a factor induced in normal fibroblasts by transforming growth factor β and overexpressed in fibrotic disease, CCN2 has been hypothesized to be not only a marker but also a central mediator of fibrosis in vivo. Finally, in vivo data are emerging to validate this key hypothesis. For example, a neutralizing anti-CCN2 antibody was found to attenuate fibrogenesis in three separate animal models (Wang et al. in Fibrogenesis Tissue Repair 4:1–4, 2011). This commentary addresses recent data indicating that CCN2 appears to represent a key central mediator of fibrosis and a good target for anti-fibrotic drug intervention.     

Estradiol receptors in breast cancer cells: Associated co-factors as targets for new therapeutic approaches

Estrogen receptors α (ERα) and β (ERβ) are nuclear receptors which transduce estradiol (E2) response in many tissues including the mammary gland and breast cancers (BC). They activate or inhibit specific genes involved in cell cycle progression and cell survival through multiple enzyme activities leading to malignant transformation. Hormone therapy (antiestrogens (AEs) and aromatase inhibitors (AIs) have been widely used to block the mitogenic action of E2 in patients with ER-positive BC. ERs act in concert with numerous other proteins outside and inside the nucleus where co-activators such as histone modifying enzymes help reaching optimum gene activation. Moreover, E2-mediated gene regulation can occur through ERs located at the plasma membrane or G protein-coupled estrogen receptor (GPER), triggering protein kinase signaling cascades. Classical AEs as well as AIs are inefficient to block the cascades of events emanating from the membrane and from E2 binding to GPER, leading patients to escape anti-hormone treatments and hormone therapy resistance. Many pathways are involved in resistance, mostly resulting from over-expression of growth factor membrane receptors, in particular the HER2/ErbB2 which can be inhibited by specific antibodies or tyrosine kinases inhibitors. Together with the Hsp90 molecular chaperone machinery, a complex interplay between ERs, co-activators, co-repressors and growth factor-activated membrane pathways represents potent targets which warrant to be manipulated alone and in combination to designing novel therapies. The discovery of new potential targets arising from micro array studies gives the opportunity to activate or inhibit different new ER-modulating effectors for innovative therapeutic interventions.     

Understanding insect endocrine systems: molecular approaches

Molecular approaches have led to spectacular improvement of our knowledge of insect endocrinology. The present review focuses on two major classes of insect lipidic hormones, ecdysteroids and juvenile hormones. Although the ecdysteroid biosynthetic pathway is not yet fully elucidated, several new steps have been recently characterized, and molecular studies of biosynthetic enzymes are now beginning. It is expected that, thanks to suitable biological models (e.g., ecdysteroid-defective mutants of Drosophila), the entire biosynthetic pathway will be elucidated in the near future. The understanding of the ecdysteroid mode of action has benefited from studies with Drosophila and major developments relate to the cascades of gene activation and the molecular basis for the stage- and tissue-specificity of hormonal effects. The biosynthetic pathway of juvenile hormones is fully known, but molecular studies of enzymes are still in their infancy, and there is some controversy about the nature of juvenile hormone receptors. Within the forthcoming years, molecular tools will allow to characterize all the enzymes involved in hormone biosynthesis and then to analyze the fine regulation of hormone titers. They will also allow comparative studies aimed at investigating the presence of related molecules (hormone biosynthetic enzymes and receptors) among other Invertebrates (Arthropods and non-Arthropods), and thus to propose evolutionary scenarios for their endocrine systems.     

Biochemical-markers for the diagnosis of bone metastasis: a clinical review

The preferential metastasis of cancer cells to skeleton not only disrupts the process of bone remodeling and influences the therapeutic decision, but also results in severe complications. Although the current diagnosis of bone metastases (BM) relies on bone imaging techniques, they are not sensitive enough for early detection as well as they are invasive and expensive to use. Since factors derived from bone metabolism are potentially useful to diagnose metastatic bone disease in cancer patients, a number of clinical trials have been carried out on this area. Results suggest that higher levels of bone biomarkers are associated with an increased risk of BM. As a result, biochemical-markers are showing prospects in early diagnosis of BM. This review summarizes the available evidence on the clinical use of biochemical-markers in the diagnosis of various cancers with high incidence of BM including breast, prostate and lung.     

Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.