The Emergence of Natural Killer Cells as a Major Target in Cancer Immunotherapy

Bone physiological microenvironment and healing mechanism: Basis for future bone-tissue engineering scaffolds.

Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

// Yun Ye 1, 2, * , Su-Liang Li 2, * , Yue-Yun Ma 1 , Yan-Jun Diao 1 , Liu Yang 1 , Ming-Quan Su 1 , Zhuo Li 2 , Yang Ji 3 , Juan Wang 1 , Lin Lei 1 , Wei-Xiao Fan 1 , La-Xiu Li 1 , Yi Xu 1 and Xiao-Ke Hao 1 1 Department of Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 2 Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi 710077, China 3 Department of Radiology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi 710077, China * These authors have contributed equally to this study Correspondence to: Xiao-Ke Hao, email: haoxkg@126.com Keywords: exosome; miR-141-3p; DLC1; p38MAPK; osteoblast activity Received: May 07, 2017     Accepted: September 05, 2017     Published: October 24, 2017 ABSTRACT Exosomes from cancer cells, which contain microRNA and reach metastasis loci prior to cancer cells, stimulate the formation of a metastatic microenvironment. Previous studies have shown that exosomal miR-141-3p is associated with metastatic prostate cancer (PCa). However, the role and regulatory mechanism of miR-141-3p in the microenvironment of bone metastases require further study. In this study, we performed a series of experiments in vivo and in vitro to determine whether exosomal miR-141-3p from MDA PCa 2b cells regulates osteoblast activity to promote osteoblastic metastasis. We demonstrate that extracts obtained from cell culture supernatants contained exosomes and that miR-141-3p levels were significantly higher in MDA PCa 2b cell exosomes. Via confocal imaging, numerous MDA PCa 2b exosomes were observed to enter osteoblasts, and miR-141-3p was transferred to osteoblasts through MDA PCa 2b exosomes in vitro . Exosomal miR-141-3p from MDA PCa 2b promoted osteoblast activity and increased osteoprotegerin OPG expression. miR-141-3p suppressed the protein levels of the target gene DLC1, indicating its functional significance in activating the p38MAPK pathway. In animal experiments, exosomal miR-141-3p had bone-target specificity and promoted osteoblast activity. Mice injected with miR-141-3p-mimics exosomes developed apparent osteoblastic bone metastasis. Exosomal miR-141-3p from MDA PCa 2b cells promoted osteoblast activity and regulated the microenvironment of bone metastases, which plays an important role in the formation of bone metastases and osteogenesis damage in PCa. Clarifying the specific mechanism of bone metastasis will help generate new possibilities for the treatment of PCa.

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Exosomal miR-141-3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer.

The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance, and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.

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Tumor Microenvironment Heterogeneity: Challenges and Opportunities

TGF-β receptors: In and beyond TGF-β signaling.

Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

/pdf/the-host-microenvironment-influences-prostate-cancer-1v0d1oygnj.pdf

The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis

Enzalutamide, a second-generation small-molecule inhibitor of the androgen receptor (AR), has been approved for patients who failed with androgen deprivation therapy and have developed castration-resistant prostate cancer. More than 80% of these patients develop bone metastases. The binding of enzalutamide to the AR prevents the nuclear translocation of the receptor, thus inactivating androgen signaling. However, prostate cancer cells eventually develop resistance to enzalutamide treatment. Studies have found resistance both in patients and in laboratory models. The mechanisms of and approaches to overcoming such resistance are significant issues that need to be addressed. In this review, we focus on the major mechanisms of acquired enzalutamide resistance, including genetic mutations and splice variants of the AR, signaling pathways that bypass androgen signaling, intratumoral androgen biosynthesis by prostate tumor cells, lineage plasticity, and contributions from the tumor microenvironment. Approaches for overcoming these mechanisms to enzalutamide resistance along with the associated problems and solutions are discussed. Emerging questions, concerns, and new opportunities in studying enzalutamide resistance will be addressed as well.

/pdf/mechanisms-and-approaches-for-overcoming-enzalutamide-2581cf6xom.pdf

Mechanisms and Approaches for Overcoming Enzalutamide Resistance in Prostate Cancer

Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis.

Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared with patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.

Xiaohong Li

Papers

TGF-β receptors: In and beyond TGF-β signaling.

The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis

Mechanisms and Approaches for Overcoming Enzalutamide Resistance in Prostate Cancer

Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis.

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3.