Potential Oncogenic Effect of the MERTK-Dependent Apoptotic-Cell Clearance Pathway in Starry-Sky B-Cell Lymphoma.

The histological architecture of certain aggressive B-cell lymphomas (prototypically Burkitt's lymphoma, BL) is characterized by a "starry-sky" (SS) appearance. This is caused by tumor-associated macrophages (TAMs), which appear in standard histological preparations as "stars" in a darkly stained "sky" of lymphoma cells. SS-TAMs accumulate in response to constitutive apoptosis in these tumors and are activated by the apoptotic tumor cells to a pro-oncogenic phenotype. The extent to which SS-TAMs contribute to lymphoma growth through responses generated by interactions with apoptotic tumor cells is unknown. Here, we demonstrate a role for the receptor tyrosine kinase, MERTK, in the oncogenic activity of SS-TAMs. We show that MERTK expression is largely restricted to the macrophages of human BL and of murine models of SS B-cell lymphoma and that it is upregulated in SS-TAMs as compared to the germinal center or paracortical macrophages of normal lymph nodes. Our results further demonstrate that MERTK is active in the phagocytosis of apoptotic lymphoma cells by macrophages and, most significantly, that SS lymphoma growth is markedly inhibited in Mertk-/- mice. These results point toward the MERTK apoptotic-cell clearance/response pathway playing a key role in growth of aggressive B-cell lymphoma and identifies MERTK as a novel potential antilymphoma target.

Opportunistic Screening of Oral Potentially Malignant Disorders: A Public Health Need for India.

PURPOSE: Oral cancer (OC) is the leading cancer in 25% of Indian cancer registries, and 80% of OCs are diagnosed in advanced stages. OC screening is a topic of debate. Studies from other countries have used a variety of study designs as OC screening strategies. There are not many studies from India on strategic screening, and there is a need to review the literature to provide insights and knowledge about screening programs. The purpose of this narrative review is to present broad epidemiologic evidence on the OC burden in India, to discuss and summarize the currently available evidence for OC screening strategies, and to highlight a feasible opportunistic screening strategy for addressing OC burden in India. METHODS: Medline and EMBASE were used to identify articles. Data from GLOBOCAN and government reports were obtained from websites. As many key concepts and divergent views cannot be addressed with a single research question, a narrative review was considered appropriate, but to ensure a comprehensive literature search, a systematic review search strategy was used. RESULTS: OC rates are rising more rapidly in India than projected. Wide variations in OC incidence within India reflect regional diversity of risk factors. Studies abroad have demonstrated the feasibility of opportunistic screening of oral potentially malignant disorders by dentists; however, although recommendations exist in India, no studies of opportunistic screening by dentists have been reported. CONCLUSION: The projected major increases in the OC burden necessitate an OC screening program; opportunistic screening of high-risk groups by dentists using oral visual examination is recommended as a cost-effective strategy. As a way forward, a pilot project to assess the feasibility of regional opportunistic screening is in progress.

An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles.

The cell-death programme, apoptosis, is well established as a tumour suppressor mechanism. Paradoxically, high levels of apoptosis in tumours are closely coupled with poor prognosis. Indeed, where it has been studied, cell loss is a striking feature of high-grade cancers, illustrating the importance of considering malignant disease as an imbalance between cell gain and cell loss that favours cell gain rather than as a unidirectional disorder of cell gain alone. In addition to orchestrating cell loss, apoptosis can signal regenerative responses-for example compensatory proliferation-in neighbouring cells. Accumulating evidence suggests that normal tissue repair and regenerative processes are hijacked in the malignant tissue microenvironment such that cancer may be likened to a 'wound that fails to stop repairing'. We have proposed that a critical requirement for the successful growth, progression and re-growth of malignant tumours is a complex milieu, conceptually termed the 'onco-regenerative niche', which is composed, in addition to transformed neoplastic cells, of a network of normal cells and factors activated as if in tissue repair and regeneration. Our work is based around the hypothesis that tumour cell apoptosis, macrophage activation and endothelial activation are key, interlinked elements of the onco-regenerative niche and that apoptotic tumour cell-derived extracellular vesicles provide critical intercellular communication vehicles of the niche. In aggressive B-cell lymphoma, tumour cell apoptosis promotes both angiogenesis and the accumulation of pro-tumour macrophages in the lymphoma microenvironment. Furthermore, apoptotic lymphoma-derived extracellular vesicles have potent pro-tumour potential. These findings have important implications for the roles of apoptosis in regulation of malignant diseases and for the efficacy of apoptosis-inducing anti-cancer therapies.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

Office design and health: a systematic review.

AIM: To carry out a systematic review of recent research into the effects of workplace design, comparing individual with shared workspaces, on the health of employees. METHODS: The research question was "Does workplace design (specifically individual offices compared with shared workspaces) affect the health of workers?" A literature search limited to articles published between 2000 and 2017 was undertaken. A systematic review was carried out, and the findings of the reviewed studies grouped into themes according to the primary outcomes measured in the studies. RESULTS: The literature search identified 15 relevant studies addressing health effects of shared or open-plan offices compared with individual offices. Our systematic review found that, compared with individual offices, shared or open-plan office space is not beneficial to employees' health, with consistent findings of deleterious effects on staff health, wellbeing and productivity. Our findings are also consistent with those of earlier reviews. CONCLUSION: These findings have public health implications for the New Zealand workforce. Decisions about workplace design should include weighing the short-term financial benefits of open-plan or shared workspaces against the significant harms, including increased sickness absence, lower job satisfaction and productivity, and possible threats to recruitment and retention of staff.

Modulation of macrophage antitumor potential by apoptotic lymphoma cells.

In aggressive non-Hodgkin's lymphoma (NHL), constitutive apoptosis of a proportion of the tumor cell population can promote net tumor growth. This is associated with the accumulation of tumor-associated macrophages (TAMs) that clear apoptotic cells and exhibit pro-oncogenic transcriptional activation profiles characteristic of reparatory, anti-inflammatory and angiogenic programs. Here we consider further the activation status of these TAMs. We compare their transcriptomic profile with that of a range of other macrophage types from various tissues noting especially their expression of classically activated (IFN-γ and LPS) gene clusters - typically antitumor - in addition to their previously described protumor phenotype. To understand the impact of apoptotic cells on the macrophage activation state, we cocultured apoptotic lymphoma cells with classically activated macrophages (M(IFN-γ/LPS), also known as M1, macrophages). Although untreated and M(IFN-γ/LPS) macrophages were able to bind apoptotic lymphoma cells equally well, M(IFN-γ/LPS) macrophages displayed enhanced ability to phagocytose them. We found that direct exposure of M(IFN-γ/LPS) macrophages to apoptotic lymphoma cells caused switching towards a protumor activation state (often referred to as M2-like) with concomitant inhibition of antitumor activity that was a characteristic feature of M(IFN-γ/LPS) macrophages. Indeed, M(IFN-γ/LPS) macrophages exposed to apoptotic lymphoma cells displayed increased lymphoma growth-promoting activities. Antilymphoma activity by M(IFN-γ/LPS) macrophages was mediated, in part, by galectin-3, a pleiotropic glycoprotein involved in apoptotic cell clearance that is strongly expressed by lymphoma TAMs but not lymphoma cells. Intriguingly, aggressive lymphoma growth was markedly impaired in mice deficient in galectin-3, suggesting either that host galectin-3-mediated antilymphoma activity is required to sustain net tumor growth or that additional functions of galectin-3 drive key oncogenic mechanisms in NHL. These findings have important implications for anticancer therapeutic approaches aimed at polarizing macrophages towards an antitumor state and identify galectin-3 as a potentially important novel target in aggressive NHL.

A Trp-BODIPY cyclic peptide for fluorescence labelling of apoptotic bodies.

The rational design and synthesis of a Trp-BODIPY cyclic peptide for the fluorescent labelling of apoptotic bodies is described. Affinity assays, confocal microscopy and flow cytometry analysis confirmed the binding of the peptide to negatively-charged phospholipids associated with apoptosis, and its applicability for the detection and characterisation of subcellular structures released by apoptotic cells.

Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.

BACKGROUND: Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. RESULTS: Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. CONCLUSIONS: In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy.

The contraceptive potential of ZP3 and ZP3 peptides in a primate model.

It has been known for some time that antibodies raised against ZP3, the major component of the glycoprotein shell that surrounds all mammalian oocytes, can successfully inhibit sperm-egg interaction in vitro. In our own studies using the non-human primate Callithrix jacchus, active immunisation was successfully achieved when homologous or heterologous ZP3 was used as an immunogen. However this long-term suppression of fertility was at the expense of ovarian function. An ovarian pathology was observed which was characterised by a disruption of folliculogenesis and depletion of the primordial follicle pool. Adverse auto-immune reactions have also been observed in mice following induction of immunity to mouse ZP3. Following careful selection of B-cell epitopes on mouse ZP3, peptide vaccines were formulated which could circumvent these adverse side effects and induce reversible infertility in actively immunised mice. To identify similar epitopes on primate ZP3, epitope mapping studies were performed and several candidate regions of the molecule were identified. These were incorporated into chimeric peptide vaccines and administered as single or triple peptide vaccines. Active immunisation successfully induced antibodies that bound exclusively to the zona pellucida of marmoset and human ovarian sections. These antibodies were able to suppress human sperm-egg binding by up to 60% in vitro. Encouragingly, no adverse side effects on ovarian function were observed following long-term immunisation however, no loss of fertility was consistently observed in vivo. Thus considerable research is still required to identify a combination of ZP epitopes that will induce reversible infertility in the absence of any ovarian dysfunction.