Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions

The mouth and oropharynx are among the ten most common sites affected by cancer worldwide, but global incidence varies widely. Five-year survival rates exceed 50% in only the best treatment centers. Causes are predominantly lifestyle-related: Tobacco, areca nut, alcohol, poor diet, viral infections, and pollution are all important etiological factors. Oral cancer is a disease of the poor and dispossessed, and reducing social inequalities requires national policies co-ordinated with wider health and social initiatives - the common risk factor approach: control of the environment; safe water; adequate food; public and professional education about early signs and symptoms; early diagnosis and intervention; evidence-based treatments appropriate to available resources; and thoughtful rehabilitation and palliative care. Reductions in inequalities, both within and between countries, are more likely to accrue from the application of existing knowledge in a whole-of-society approach. Basic research aimed at determining individual predisposition and acquired genetic determinants of carcinogenesis and tumor progression, thus allowing for targeted therapies, should be pursued opportunistically.     

Report: workshop on mediastinal grey zone lymphoma

There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in-between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL-13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so-called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL.     

Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors

Alternative splicing of proteins gives rise to different isoforms that play a crucial role in regulating several cellular processes. Notably, splicing profiles are altered in several cancer types, and these profiles are believed to be involved in driving the oncogenic process. Although the importance of alternative splicing alterations occurring during cancer is increasingly appreciated, the underlying regulatory mechanisms remain poorly understood. In this study, we use both biochemical and physical tools coupled with engineered models, patient samples, and a murine model to investigate the role of the mechanical properties of the tumor microenvironment in regulating the production of the extra domain-B (EDB) splice variant of fibronectin (FN), a hallmark of tumor angiogenesis. Specifically, we show that the amount of EDB-FN produced by endothelial cells increases with matrix stiffness both in vitro and within mouse mammary tumors. Matrix stiffness regulates splicing through the activation of serine/arginine rich (SR) proteins, the splicing factors involved in the production of FN isoforms. Activation of the SR proteins by matrix stiffness and the subsequent production of EDB-FN are dependent on intracellular contractility and PI3K-AKT signaling. Notably, matrix stiffness-mediated splicing is not limited to EDB-FN, but also affects splicing in the production of PKC βII and the VEGF 165b splice variant. Together, these results demonstrate that the mechanical properties of the microenvironment regulate alternative splicing and establish a previously unidentified mechanism by which cells can adapt to their microenvironment.Differential expression of protein isoforms through alternative splicing is a key element to generating protein diversity and can result in widely different cell phenotypes and behaviors (1–3). Interestingly, tumors exhibit several major differences in protein isoform expression patterns compared with healthy tissue (2, 4), and some of these changes are thought to favor oncogenesis (1). Notably, splicing events are regulated at the pre-mRNA level by splicing regulatory factors that include a family of serine/arginine rich (SR) proteins (5). Elevated SR protein levels have been associated with cancer (5); however, the physiological cues that drive splicing are not well defined.Among the various alternatively spliced proteins present in tumors, the splice variant of fibronectin (FN) that includes the extra domain-B (EDB) type III repeat has been of particular interest in the cancer community because inclusion of the EDB fragment has been proposed as a way to identify and target tumor vasculature (6). EDB-FN is produced by endothelial cells (ECs) in tumors and may favor angiogenesis (7–9). Splicing of FN is regulated by several SR proteins, including SRp40 and SRp20, in several different cell types (10–12). Although the presence of EDB-FN is fairly unique to tumor vasculature, the mechanisms governing its expression within the tumor microenvironment are not clear.The splicing activity of SR proteins that leads to the expression of various protein isoforms including EDB-FN is tightly regulated by phosphorylation (13–15), and this phosphorylation has been shown to be mediated by AKT (14, 16). Interestingly, matrix stiffness can regulate AKT phosphorylation state (17–19). More specifically, recent data indicate that AKT activation and downstream phosphorylation of AKT substrates can occur through changes in the mechanical properties of the tissue in the tumor microenvironment (17). Importantly, tumor tissue stiffens during cancer due to increased collagen deposition and the action of cell-secreted enzymes that cross-link collagen fibrils (20, 21), and this stiffening is believed to be correlated with tumor aggressiveness and metastatic potential (18, 22–25). Elevated extracellular matrix (ECM) stiffness affects several cell behaviors associated with tumors including enhanced cell contractility, response to growth factors, and cell migration (18, 22, 24, 26, 27). Although stiffness has been shown to drive greater AKT activation, AKT activity drives SR protein phosphorylation, and SR proteins mediate splicing, it has not yet been determined whether stiffness-driven signaling can result in SR protein-mediated splicing events during tumorigenesis.In this study, we used a multidisciplinary approach, with in vitro and in vivo models and biochemical and physical tools, to study the relationship between matrix stiffness and FN splicing in ECs. Here, we demonstrate, for the first time to our knowledge, that EDB-FN expression increases with matrix stiffness, both in vitro and in mouse mammary tumors. Our data indicate that matrix stiffness regulates the dynamics of EDB-FN splicing through Rho-associated protein kinase (ROCK) mediated contractility and downstream SR protein phosphorylation. Moreover, phosphorylation of SR proteins correlates with in vivo PI3K/AKT pathway activity in response to tissue stiffness, whereas in vitro inhibition of PI3K prevents SR protein phosphorylation and EDB-FN splicing. Taken together, our data show, for the first time to our knowledge, that the stiffness of the tumor microenvironment modulates intracellular splicing events.     

Implanted adipose progenitor cells as physicochemical regulators of breast cancer

Multipotent adipose-derived stem cells (ASCs) are increasingly used for regenerative purposes such as soft tissue reconstruction following mastectomy; however, the ability of tumors to commandeer ASC functions to advance tumor progression is not well understood. Through the integration of physical sciences and oncology approaches we investigated the capability of tumor-derived chemical and mechanical cues to enhance ASC-mediated contributions to tumor stroma formation. Our results indicate that soluble factors from breast cancer cells inhibit adipogenic differentiation while increasing proliferation, proangiogenic factor secretion, and myofibroblastic differentiation of ASCs. This altered ASC phenotype led to varied extracellular matrix (ECM) deposition and contraction thereby enhancing tissue stiffness, a characteristic feature of breast tumors. Increased stiffness, in turn, facilitated changes in ASC behavior similar to those observed with tumor-derived chemical cues. Orthotopic mouse studies further confirmed the pathological relevance of ASCs in tumor progression and stiffness in vivo. In summary, altered ASC behavior can promote tumorigenesis and, thus, their implementation for regenerative therapy should be carefully considered in patients previously treated for cancer.     

Left ventricular assist device-associated infections

The left ventricular assist device (LVAD) is a mechanical pump that supplements or replaces the function of a damaged left ventricle. Although LVAD support is associated with improved survival and quality of life, infectious complications remain a major limitation. The authors examine the epidemiology of LVAD-associated infections and review current diagnostic, treatment, and management strategies. Novel evidence-based approaches to infection prevention remain critical because the number of patients receiving long-term mechanical support continues to burgeon.