Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

Extracellular vesicles (EVs) are nanosized particles released by numerous kinds of cells, which are now increasingly considered as essential vehicles of cell-to-cell communication and biomarkers in disease diagnosis and treatment. They contain a variety of biomolecular components, including lipids, proteins and nucleic acids. These functional molecules can be transmitted between tumor cells and other stromal cells such as endothelial cells, fibroblasts and immune cells utilizing EVs. As a result, tumor-derived EVs can deliver molecules to remodel the tumor microenvironment, thereby influencing cancer progression. On the one hand, tumor-derived EVs reprogram functions of endothelial cells, promote cancer-associated fibroblasts transformation, induce resistance to therapy and inhibit the immune response to form a pro-tumorigenic environment. On the other hand, tumor-derived EVs stimulate the immune response to create an anti-tumoral environment. This article focuses on presenting a comprehensive and critical overview of the potential role of tumor-derived EVs-mediated communication in the tumor microenvironment.

Common pathways and functional profiles reveal underlying patterns in Breast, Kidney and Lung cancers

Background : Cancer is an extremely heterogeneous disease, both intra and inter cancer types. In this work we aim to establish common patterns in Breast, Kidney and Lung cancers at the signaling pathways and functional level which give rise to the generic microenvironment of cancer, as well as determine cancer-specific pathways and functions related to each disease. Results : After a tumor vs. normal tissue comparison of the levels of activation of the signaling pathways and cell functions, we found a significant number of common subpathways and functions related to the three studied tumors. Also common survival mechanisms were established. Cancer-specific features which are only significant in one of the tumors have been determined. Conclusions : The joint analysis of these different cancer datasets reported an appreciable number of common functional features, some of them related at the same time to survival in two of the three analyzed cancers. On the other hand, tumor-specific subpathways and functions have been determined, allowing a better understanding of the specificity of each cancer. Keywords : cancer, signaling, pathways, functional analysis, common

Endothelial sphingosine 1-phosphate receptors promote vascular normalization and antitumor therapy

Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO, whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1pr1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.

Precision of customized surgical osteotomy guide (CSOG) in mandibular reconstruction with a customized implant

Purpose This study aims to find the usefulness of the customized surgical osteotomy guide (CSOG) for accurate mandibular tumor resection for boosting the accuracy of prefabricated customized implant fixation in mandibular reconstructions. Design/methodology/approach In all, 30 diseased mandibular RP models (biomodels) were allocated for the study (for experimental group [n = 15] and for control group [n = 15]). To reconstruct the mandible with customized implant in the experimental group, CSOGs and in control group, no CSOG were used for accurate tumor resections. In control group, only preoperative virtual surgical planning (VSP) and reconstructed RP mandible model were used for the reference. Individually each patient’s preoperative mandibular reconstructions data of both the groups were superimposed to the preoperative VSP of respective patient by registering images with the non-surgical side of the mandible. In both the groups, 3D measurements were taken on the reconstructed side and compared the preoperative VSP and postoperative reconstructed mandible data. The sum of the differences between pre and postoperative data was considered as the total error. This procedure was followed for both the groups and compared the obtained error between the two groups using statistical analysis. Findings The use of CSOG for accurate tumor resection and exact implant fixation in mandibular reconstruction produced a smaller total error than without using CSOG. Originality/value The results showed that, benefits provided with the use of CSOG in mandibular reconstruction justified its use over the without using CSOG, even in free hand tumor resection using rotating burr.

Functions of Exosomes in the Triangular Relationship between the Tumor, Inflammation, and Immunity in the Tumor Microenvironment

Exosomes are extracellular vesicles that contain diverse components such as genetic materials, proteins, and lipids. Owing to their distinct derivation and tissue specificity, exosomes act as double-edged swords during the development of neoplasms. On the one hand, tumor-derived exosomes can modulate the immune system during tumorigenesis by regulating inflammatory cell infiltration and oxidative stress and by promoting epithelial-to-mesenchymal transition and immune-induced tumor dormancy. On the other hand, components of specific immune cell-derived exosomes may contribute to the efficacy of antitumor immunotherapy. In this review, we demonstrate the pivotal role of exosomes in the triangular relationship in the tumor microenvironment between the tumor, inflammation, and immunity, which may provide potential strategies for tumor immunotherapy at genetic and cellular levels.

Endothelial sphingosine 1-phosphate receptors promote vascular normalization to influence tumor growth and metastasis

Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1pr1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy.SignificanceEndothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.

Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis

Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can “educate” platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression.