Metastatic cancers produce exosomes that condition pre-metastatic niches in remote microenvironments to favor metastasis. In contrast, here we show that exosomes from poorly metastatic melanoma cells ...can potently inhibit metastasis to the lung. These "non-metastatic" exosomes stimulate an innate immune response through the expansion of Ly6C
patrolling monocytes (PMo) in the bone marrow, which then cause cancer cell clearance at the pre-metastatic niche, via the recruitment of NK cells and TRAIL-dependent killing of melanoma cells by macrophages. These events require the induction of the Nr4a1 transcription factor and are dependent on pigment epithelium-derived factor (PEDF) on the outer surface of exosomes. Importantly, exosomes isolated from patients with non-metastatic primary melanomas have a similar ability to suppress lung metastasis. This study thus demonstrates that pre-metastatic tumors produce exosomes, which elicit a broad range of PMo-reliant innate immune responses via trigger(s) of immune surveillance, causing cancer cell clearance at the pre-metastatic niche.
We have previously demonstrated that apigenin promotes the expression of antiangiogenic protein thrombospondin-1 (TSP1) via a mechanism driven by mRNA-binding protein HuR. Here, we generated a novel ...mouse model with whole-body THBS-1 gene knockout on SKH-1 genetic background, which allows studies of UVB-induced acute skin damage and carcinogenesis and tests TSP1 involvement in apigenin's anticancer effects. Apigenin significantly inhibited UVB-induced carcinogenesis in the wild-type (WT) animals but not in TSP1 KO (TKO) mice, suggesting that TSP1 is a critical component of apigenin's chemopreventive function in UVB-induced skin cancer. Importantly, TKO mice presented with the elevated cutaneous inflammation at baseline, which was manifested by increased inflammatory infiltrates (neutrophils and macrophages) and elevated levels of the two key inflammatory cytokines, IL-6 and IL-12. In agreement, maintaining normal TSP1 expression in the UVB-irradiated skin of WT mice using topical apigenin application caused a marked decrease of circulating inflammatory cytokines. Finally, TKO mice showed an altered population dynamics of the bone marrow myeloid progenitor cells (CD11b+), with dramatic expansion of the population of neutrophil progenitors (Ly6ClowLy6Ghigh) compared to the WT control. Our results indicate that the cutaneous tumor suppressor TSP1 is a critical mediator of the in vivo anticancer effect of apigenin in skin, specifically of its anti-inflammatory action.
The relevance of the topic is due to the fact that traditional social disciplines have not been able to solve the most important problems of humanity – the elimination of destructive forms of social ...interactions. The article deals with the problem of conceptualization of the concept of “peace”, the stages of formation of the disciplinary field of peace research. The hypothesis of the study is that understanding the initial intention that prompts the formation of new value orientations in human populations makes it possible to base the modern theory of the world on the concept of existential security. The purpose of the article is to analyze approaches to one of the basic concepts of social and humanitarian disciplines ‒ the category of peace. The use of methods of categorization, retrospective analysis and systematization allowed us to discover the paradigmatic dependence of the content of the concept peace on objective technological and socio-cultural circumstances. The results of the discussion were the following provisions. The first concept of peace, called the negative peace, could not be used as the basis for social construction programs, since it carried all the limitations of the classical paradigm of science, which was formed to serve natural science. The modern, third generation of the concept of peace, which has received the complex name of a multi-inter-transcultural world, is generated by the dangers associated with globalization and entry into digital civilization. Understanding the initial intention that encourages the formation of new value orientations in human populations allows us to base the modern theory of the world on the concept of existential security. The concept of existential security is formulated, which should be understood not as the physical security of an individual, but as the security of the existence of a population that allows preserving the population gene pool. A society that has provided existential security corresponds to people’s ideas of peaceful existence and does not create conditions for war, as one of the forms of violence, or for other forms of structural violence that reduce the adaptive potential of the population. Due to the fact that the adaptability and security of the digital society is ensured by the integrative and communitarian properties of the social system, post-material values are put forward in the first place in the value system in the modern world. They should be the basis of the concept of the existential world.
Exosomes are produced by cells to mediate intercellular communication, and have been shown to perpetuate diseases, including cancer. New tools are needed to understand exosome biology, detect ...exosomes from specific cell types in complex biological media, and to modify exosomes. Our data demonstrate a cellular pathway whereby membrane-bound scavenger receptor type B-1 (SR-B1) in parent cells becomes incorporated into exosomes. We tailored synthetic HDL-like nanoparticles (HDL NP), high-affinity ligands for SR-B1, to carry a fluorescently labeled phospholipid. Data show SR-B1-dependent transfer of the fluorescent phospholipid from HDL NPs to exosomes. Modified exosomes are stable in serum and can be directly detected using flow cytometry. As proof-of-concept, human serum exosomes were found to express SR-B1, and HDL NPs can be used to label and isolate them. Ultimately, we discovered a natural cellular pathway and nanoparticle-receptor pair that enables exosome modulation, detection, and isolation.
Abstract
Purpose: Ovarian cancer is the deadliest gynecologic malignancy with limited treatment options and novel therapies urgently needed. Immunosuppressive microenvironment is critical for tumor ...progression and immune checkpoint inhibitors, which enable T-cell anticancer immunity revolutionized the outcomes in multiple cancer types. However, this approach had limited success in ovarian cancer. Our small therapeutic peptides, derived from an endogenous type 2 tumor suppressor, Pigment Epithelium-Derived Factor (PEDF), act through an alternative immune mechanism, repolarization of tumor-associated macrophages (TAMs) to the tumor-suppressive phenotype.Experimental Design: Short peptides based on the PEDF's active domain were modified for improved stability and efficacy. Two peptides (PMD-427, PMD-336) were tested in preclinical ovarian cancer models using the human chemoresistant cell line, OvCar-3, and transformed mouse cell line ID8. We also performed mechanistic analysis of the peptides' anti-tumor action, including effects on macrophages cytotoxic, cytokine secretion and migratory activity in vitro and in vivo. Results: PEDF peptide PMD-427 caused > 20-fold reduction in tumor burden. PMD-427 induced selective apoptosis in ovarian cancer cells but not in normal ovarian epithelium. This selectivity was based on context-specific modulation of extrinsic death cascades, Fas and FasL. More importantly, PMD-427 peptides also stimulated macrophage polarization from M2 to M1 phenotype as was evidenced by the shift in cytokine profile (decreased IL-10 and increased IL-12 expression), altered morphology (increased number of dendrite-like-processes) and other changes in M2 markers (attenuated PD-L1 expression). M2/M1 macrophage polarization was also evident by tumor immunostaining. Critically, PMD peptides ovarian cancer cell killing by macrophages as was determined in co-culture studies; this fratricidal activity was reliant on the expression of TRAIL by the macrophages and of its cognate receptor, DR5 by ovarian cancer cells, respectively. Combined with enhanced macrophage motility as observed by time-lapse micropscopy, these changes resulted in increased macrophage recruitment to the tumors and enhance killing of the cancer cells in vivo. The key role of macrophages in the anti-cancer effects of PMD peptides was confirmed by depletion of macrophages in ovarian tumor bearing mice using clodronate liposomes. Conclusions: We have generated a first-in-class multi-targeted peptide drug, which promotes macrophage polarization that results in eradication of ovarian tumors in mice.
Citation Format: Reshma Bhowmick, Elena Vinokour, Michael Paul Plebanek, Marisol Villanueva, Victor Shifrin, Jack Henkin, Ignacio Melgar-Asensio, James Petrik, Raghu Kallurie, Olga V. Volpert. Reprogramming of tumor-associated macrophages by a short synthetic peptide eradicates ovarian cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3133.
The philosophical category of values has not yet been subject to natural-scientific verification. The impossibility or limited application of criteria and methodology of natural sciences to the study ...of phenomena of spiritual existence significantly hinders the development of humanitarian knowledge. The study of the nature of values through the study of human behavior introduces ideational objects into the nomothetic field, which allows us to verify the philosophical concepts of values. The study was aimed at assessing the role of life satisfaction as a moderator of the relationship between consumer ethnocentrism and the attitude to domestic goods purchase in an alternative choice situation.
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