Mast Cell Modulation of B Cell Responses: An Under-Appreciated Partnership in Host Defence.

Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.

Mast Cells and Skin and Breast Cancers: A Complicated and Microenvironment-Dependent Role.

Mast cells are important sentinel cells in host defense against infection and major effector cells in allergic disease. The role of these cells in cancer settings has been widely debated. The diverse range of mast cell functions in both immunity and tissue remodeling events, such as angiogenesis, provides multiple opportunities for mast cells to modify the tumor microenvironment. In this review, we consider both skin and breast cancer settings to address the controversy surrounding the importance of mast cells in the host response to tumors. We specifically address the key mediators produced by mast cells which impact tumor development. The role of environmental challenges in modifying mast cell responses and opportunities to modify mast cell responses to enhance anti-tumor immunity are also considered. While the mast cell's role in many cancer contexts is complicated and poorly understood, the activities of these tissue resident and radioresistant cells can provide important opportunities to enhance anti-cancer responses and limit cancer development.

TAp73 Modifies Metabolism and Positively Regulates Growth of Cancer Stem-Like Cells in a Redox-Sensitive Manner.

PURPOSE: Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anticancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells remain unknown.Experimental Design: This study utilizes various in vitro molecular biology techniques, including immunoblotting, qRT-PCR, and mass spectrometry-based proteomics, and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLC) as well as human breast cancer stem-like cells (BCSLC). These findings were confirmed using patient-derived brain tumor-initiating cells (BTIC) and in vivo xenograft models. RESULTS: TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog, and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo, TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT, and PYCR1 involved in the interconversion of proline-glutamine-ornithine. Further, TAp73 deficiency exacerbates glutamine dependency, enhances accumulation of reactive oxygen species through reduced superoxide dismutase 1 (SOD1) expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of prosurvival factors Sox-2, BMI-1, and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability. CONCLUSIONS: Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming.

HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells.

Cancer stem-like cells (CSCs), a small population of pluripotent cells residing within heterogeneous tumor mass, remain highly resistant to various chemotherapies as compared to the differentiated cancer cells. It is being postulated that CSCs possess unique molecular mechanisms, such as autophagic homeostasis, that allow CSCs to withstand the therapeutic assaults. Here we demonstrate that HDAC6 inhibition differentially modulates macroautophagy/autophagy in CSCs as compared to that of differentiated cancer cells. Using human and murine CSC models and differentiated cells, we show that the inhibition or knockdown (KD) of HDAC6 decreases CSC pluripotency by downregulating major pluripotency factors POU5F1, NANOG and SOX2. This decreased HDAC6 expression increases ACTB, TUBB3 and CSN2 expression and promotes differentiation in CSCs in an apoptosis-independent manner. Mechanistically, HDAC6 KD in CSCs decreases pluripotency by promoting autophagy, whereas the inhibition of pluripotency via retinoic acid treatment, POU5F1 or autophagy-related gene (ATG7 and ATG12) KD in CSCs decreases HDAC6 expression and promotes differentiation. Interestingly, HDAC6 KD-mediated CSC growth inhibition is further enhanced in the presence of autophagy inducers Tat-Beclin 1 peptide and rapamycin. In contrast to the results observed in CSCs, HDAC6 KD in differentiated breast cancer cells downregulates autophagy and increases apoptosis. Furthermore, the autophagy regulator p-MTOR, upstream negative regulators of p-MTOR (TSC1 and TSC2) and downstream effectors of p-MTOR (p-RPS6KB and p-EIF4EBP1) are differentially regulated in CSCs versus differentiated cancer cells following HDAC6 KD. Overall these data identify the differential regulation of autophagy as a molecular link behind the differing chemo-susceptibility of CSCs and differentiated cancer cells.

A novel ultra high molecular weight polyethylene-hyaluronan microcomposite for use in total joint replacements. I. Synthesis and physical/chemical characterization.

A novel microcomposite between ultra high molecular weight polyethylene (UHMWPE) and hyaluronan (HA) was developed to create a hydrophilic and lubricious UHMWPE surface for total joint replacement and other biomedical load-bearing applications. Preforms with interconnected micropores were used as the UHMWPE starting material to form a microcomposite with HA, rather than starting with fully dense, bulk UHMWPE. HA was silylated first to increase its hydrophobicity and compatibility with UHMWPE. The silylated groups were removed through hydrolysis prior to final compression molding. A uniform and enzymatic degradation resistant HA film layer was produced on the microcomposite surface, which quickly hydrated in water, forming a lubricious surface film that was fully wetted by water drops during contact angle measurements. Presence of HA film on the composite surface was also demonstrated through X-ray photoelectron spectroscopy analysis and Toluidine Blue O dye assay. The mechanical and tribological properties evaluation of the novel microcomposites are presented in Part II.