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// Tingting Huang 1 , Li Sun 1 , Xianglin Yuan 1 and Hong Qiu 1 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China Correspondence to: Hong Qiu, email: tjqiuhong@163.com Keywords: thrombospondin-1, tumor progression, tumor angiogenesis, cancer cell behavior, tumor immunity Received: March 16, 2017 Accepted: June 28, 2017 Published: July 11, 2017 ABSTRACT Thrombospondins are a family of extracellular matrix (ECM) proteins. Thrombospondin-1 (TSP1) was the first member to be identified and is a main player in tumor microenvironment. The diverse functions of TSP1 depend on the interactions between its structural domains and multiple cell surface molecules. TSP1 acts as an angiogenesis inhibitor by stimulating endothelial cell apoptosis, inhibiting endothelial cell migration and proliferation, and regulating vascular endothelial growth factor bioavailability and activity. In addition to angiogenesis modulation, TSP1 also affects tumor cell adhesion, invasion, migration, proliferation, apoptosis and tumor immunity. This review discusses the multifaceted and sometimes opposite effects of TSP1 on tumor progression depending on the molecular and cellular composition of the microenvironment. Clinical implications of TSP1-related compounds are also discussed.

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.

// Ruben Fernandez-Rodriguez 1 , Francisco Javier Rodriguez-Baena 1 , Estefania Martino-Echarri 1 , Carlos Peris-Torres 1 , Maria del Carmen Plaza-Calonge 1 , Juan Carlos Rodriguez-Manzaneque 1 1 GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucia, Granada 18016, Spain Correspondence to: Juan Carlos Rodriguez-Manzaneque, email: juancarlos.rodriguez@genyo.es Keywords: extracellular protease, extracellular matrix, hypoxia, tumor stroma, vasculature Received: February 24, 2016 Accepted: April 10, 2016 Published: April 22, 2016 ABSTRACT The matrix metalloprotease ADAMTS1 ( A Disintegrin And Metalloprotease with ThromboSpondin repeats 1 ) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1.

Retinoblastoma (RB) arises from the retina, and its growth usually occurs under the retina and toward the vitreous. Ideal therapy should aim to inhibit the tumor and protect neural cells, increasing the patient's life span and quality of life. Previous studies have demonstrated that Thrombospondin-1 (TSP-1) is associated with neurogenesis, neovascularization and tumorigenesis. However, at present, the bioactivity of TSP-1 in retinoblastoma has not been defined. Herein, we demonstrated that TSP-1 was silenced in RB cell lines and clinical tumor samples. HDAC inhibitor, Trichostatin A (TSA), could notably transcriptionally up-regulate TSP-1 in RB cells, WERI-Rb1 cells and Y79 cells. Moreover, we found human recombinant TSP-1 (hTSP-1) could significantly inhibit the cell viability of RB cells both in vitro and in vivo. Interestingly, hTSP-1 could significantly induce the expression of γ-H2AX, a well-characterized in situ marker of DNA double-strand breaks (DSBs) in RB cells. The DNA NHEJ pathway in WERI-Rb1 cells could be significantly inhibited by hTSP-1. A mutation in Rb1 might be involved in the hTSP-1-medicated γ-H2AX increasing in WERI-Rb1 cells. Furthermore, hTSP-1 could inhibit RB cells while promoting retinal neurocyte survival in the neuronal and retinoblastoma cell co-culture system. As such, TSP-1 may become a therapeutic target for treatment of retinoblastoma.

Our previous studies have suggested that harboring a soluble coxsackie-adenovirus receptor-ligand (sCAR-ligand) fusion protein expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting to serotype 5 adenovirus infection. We report here a novel oncolytic adenovirus vector redirected to CD47+ leukemia cells though carrying a sCAR-4N1 expression cassette in the viral genome, forming Ad.4N1, in which 4N1 represents the C-terminal CD47-binding domain of thrombospondin-1. The infection and cytotoxicity of Ad.4N1 in leukemia cells were determined to be mediated by the 4N1-CD47 interaction. Ad.4N1 was further engineered to harbor a gene encoding melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), forming Ad.4N1-IL24, which replicated dramatically faster than Ad.4N1, and elicited significantly enhanced antileukemia effect in vitro and in a HL60/Luc xenograft mouse model. Our data suggest that Ad.4N1 could act as a novel oncolytic adenovirus vector for CD47+ leukemia targeting gene transfer, and Ad.4N1 harboring anticancer genes may provide novel antileukemia agents.

// Sun Ah Ham 1 , Taesik Yoo 1 , Won Jin Lee 1 , Jung Seok Hwang 1 , Jinwoo Hur 1 , Kyung Shin Paek 2 , Dae-Seog Lim 3 , Sung Gu Han 1 , Chi-Ho Lee 1 and Han Geuk Seo 1 1 Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Korea 2 Department of Nursing, Semyung University, Jechon 27136, Korea 3 Department of Biotechnology, CHA University, Seongnam 13488, Korea Correspondence to: Han Geuk Seo, email: hgseo@konkuk.ac.kr Keywords: a disintegrin and metalloprotease domains with thrombospondin motifs 1, breast cancer cells, metastasis, peroxisome proliferator-activated receptor δ, thrombospondin-1 Received: July 04, 2017 Accepted: September 21, 2017 Published: October 06, 2017 ABSTRACT Migration and invasion of cancer cells into surrounding tissue is a key stage of cancer metastasis. Here, we show that peroxisome proliferator-activated receptor (PPAR) δ regulates migration and invasion of human breast cancer cells via thrombospondin-1 (TSP-1) and its degrading protease, a disintegrin and metalloprotease domains with thrombospondin motifs 1 (ADAMTS1). Activation of PPARδ by GW501516, a specific ligand for PPARδ, led to marked inhibition in the cell migration and TSP-1 expression of breast cancer. These effects were suppressed by small interfering RNA-mediated knock-down of ADAMTS1, indicating that ADAMTS1 is involved in PPARδ-mediated inhibition of migration and TSP-1 expression in breast cancer cells. In addition, ligand-activated PPARδ upregulated expression of ADAMTS1 at the transcriptional level via binding of PPARδ to a direct repeat-1 site within the ADAMTS1 gene promoter. Furthermore, ligand-activated PPARδ suppressed invasion of breast cancer cells in an ADAMTS1-dependent manner. Taken together, these results demonstrate that PPARδ suppresses migration and invasion of breast cancer cells by downregulating TSP-1 in a process mediated by upregulation of ADAMTS1.

// Chuanzhen Hu 1, 2, * , Junxiang Wen 1, 2, * , Liangzhi Gong 1, 2, * , Xu Chen 1, 3 , Jun Wang 2 , Fangqiong Hu 2 , Qi Zhou 2 , Jing Liang 2 , Li Wei 2 , Yuhui Shen 1, 2, ** and Weibin Zhang 1, 2, ** 1 Department of Orthopaedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China 2 Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Orthopedics and Traumatology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China 3 Wuxi Xinrui Hospital, Department of Orthopaedics, Wuxi Branch, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Wuxi 214028, People’s Republic of China * Contributed to this work equally as first author ** Contributed to this work equally as corresponding author Correspondence to: Weibin Zhang, email: weibin@medmail.com.cn Yuhui Shen, email: yuhuiss@163.com Keywords: thrombospondin-1, osoteosarcoma, lung metastasis, FAK Received: February 20, 2017 Accepted: March 24, 2017 Published: April 26, 2017 ABSTRACT Microenvironment at the metastatic locus usually differs greatly from that present in the site of primary tumor formation and it has a significant impact on the fate of the extravasated cancer cells. We compared gene expression signatures of primary tumors and lung metastatic tumors, and identified Thrombospondin-1 (TSP1) as highly up-regulated in the lung metastatic tumors. Immunohistochemical staining further indicated that TSP1 protein expression was higher in lung metastatic tumors compared to primary tumors in both osteosarcoma xenograft model and human clinical samples. TSP1 mRNA level is significantly associated with the Enneking stage of osteosarcoma and lung metastasis. TGF-β pathways could stimulate the TSP1 expression in osteosarcoma cells. Knockdown of TSP1 expression in osteosarcoma cells dramatically suppressed cell wound healing, migration and invasion. Treatment with recombinant TSP1 protein in osteosarcoma cells significantly promoted cell wound healing, migration and invasion. Meanwhile, suppression of TSP1 in osteosarcoma cells resulted in decreased pulmonary metastasis in vivo . Mechanistically, TSP1 increased expression of metastasis related genes, including MMP2, MMP9 and Fibronectin 1. TSP1 promoted osteosarcoma cell motility through the activation of FAK pathway. Taken together, our study provides evidence of the contributions of TSP1 to the lung metastasis of osteosarcoma and suggests that this protein may represent a potential therapeutic target for osteosarcoma lung metastasis.

// Jon-Vidar Gaustad 1 , Trude G. Simonsen 1 , Lise Mari K. Andersen 1 , Einar K. Rofstad 1 1 Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Correspondence to: Jon-Vidar Gaustad, email: Jon.Vidar.Gaustad@rr-research.no Keywords: malignant melanoma, thrombospondin-1, properdistatin, tumor vasculature, intravital microscopy Received: August 11, 2016 Accepted: October 12, 2016 Published: October 15, 2016 ABSTRACT In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function.

BRAFV600E is a constitutively active onco-kinase and is the most common genetic alteration in papillary thyroid carcinoma (PTC), and in anaplastic thyroid carcinoma as well, albeit at a lower frequency. The BRAFV600E mutation in some studies has been significantly associated with extra-thyroidal extension, metastases, recurrence, and mortality in patients with PTC. A recent genome-wide expression profiling approach (Gene Set Enrichment Analysis (GSEA)) and in vitro and in vivo functional studies revealed that BRAFV600E affects extracellular matrix composition (i.e. increased expression of some collagens and laminins) and promotes thyroid cancer migration and invasion. BRAFV600E through the phospho-MEK1/2 and phospho-ERK1/2 pathway may control a network of genes crucial in integrating and regulating the extracellular and intracellular signaling in thyroid cancer cells, which may be fundamental to trigger an abnormal cell differentiation/totipotency and shape/polarity, and contribute to tumor aggressiveness mechanisms (i.e. cell adhesion, migration, and invasion). Increasing our knowledge of BRAFV600E-modulated ECM genes and targeting the subset of genes essential for tumor aggressiveness will help establish a novel paradigm for treatment of thyroid cancers harboring BRAFV600E. Furthermore, identifying downstream events from the BRAFV600E/ERK1/2 pathway will eventually identify novel biomarkers that can be used to correlate with disease outcome and overall survival.