scholarly journals Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

2020 ◽  
Author(s):  
Bethany A. Kerr ◽  
Koran S. Harris ◽  
Lihong Shi ◽  
Jeffrey S. Willey ◽  
David R. Soto-Pantoja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Bone Formation ◽  
Tumor Growth ◽  
Tumor Size ◽  
Metastatic Niche ◽  
Primary Tumors ◽  
Niche Formation ◽  
Cell Mobilization ◽  
Tgf Β1

ABSTRACTThe development of distant metastasis is the main cause of prostate cancer (CaP)-related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-β1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-β1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-β1. Similar to TSP-1 deletion, loss of platelet TGF-β1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release. Within the bone microenvironment, platelet TGF-β1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-β1 axis regulates pre-metastatic niche formation and tumor-induced bone turnover. Targeting the platelet release of TSP-1 or TGF-β1 represents a potential method to interfere with the process of CaP metastasis to bone.

Perioperative Activation of Disseminated Tumor Cells in Bone Marrow of Patients With Prostate Cancer

2009 ◽  
Vol 27 (10) ◽  
pp. 1549-1556 ◽  
Author(s):  
Dorothea Weckermann ◽  
Bernhard Polzer ◽  
Thomas Ragg ◽  
Andreas Blana ◽  
Günter Schlimok ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Cox Regression ◽  
Systemic Disease ◽  
Disseminated Tumor Cells ◽  
Comparative Genomic ◽  
Prognostic Impact ◽  
Primary Tumors ◽  
Cox Regression Analysis

Purpose The outcome of prostate cancer is highly unpredictable. To assess the dynamics of systemic disease and to identify patients at high risk for early relapse we followed the fate of disseminated tumor cells in bone marrow for up to 10 years and genetically analyzed such cells isolated at various stages of disease. Patients and Methods Nine hundred bone marrow aspirates from 384 patients were stained using the monoclonal antibody A45-B/B3 directed against cytokeratins 8, 18, and 19. Log-rank statistics and Cox regression analysis were applied to determine the prognostic impact of positive cells detected before surgery (244 patients) and postoperatively (214 patients). Samples from primary tumors (n = 55) and single disseminated tumor cells (n = 100) were analyzed by comparative genomic hybridization. Results Detection of cytokeratin-positive cells before surgery was the strongest independent risk factor for metastasis within 48 months (P < .001; relative risk [RR], 5.5; 95% CI, 2.4 to 12.9). In contrast, cytokeratin-positive cells detected 6 months to 10 years after radical prostatectomy were consistently present in bone marrow with a prevalence of approximately 20% but had no influence on disease outcome. Characteristic genotypes of cytokeratin-positive cells were selected at manifestation of metastasis. Conclusion Cytokeratin-positive cells in the bone marrow of prostate cancer patients are only prognostically relevant when detected before surgery. Because we could not identify significant genetic differences between pre- and postoperatively isolated tumor cells before manifestation of metastasis, we postulate the existence of perioperative stimuli that activate disseminated tumor cells. Patients with cytokeratin-positive cells in bone marrow before surgery may therefore benefit from adjuvant therapies.

scholarly journals Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 874 ◽  
Author(s):  
Jiangang Zhao ◽  
Hans A. Schlößer ◽  
Zhefang Wang ◽  
Jie Qin ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cells ◽  
Extracellular Vesicles ◽  
Nk Cell ◽  
Killer Cell ◽  
Pancreatic Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Metastatic Niche ◽  
Niche Formation ◽  
Tgf Β1

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.

scholarly journals In Vivo Genome-Wide Crispr Library Screen in a Xenograft Mouse Model of Tumor Growth and Metastasis of Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1137-1137
Author(s):  
Yujia Shen ◽  
Salomon Manier ◽  
Jihye Park ◽  
Yuji Mishima ◽  
Marzia Capelletti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Primary Tumors ◽  
In Vivo Screening ◽  
Genome Wide ◽  
Tumor Growth And Metastasis ◽  
Early Primary

Abstract Introduction: Recent data show that Multiple Myeloma (MM) always progresses from a precursor state (monoclonal gammopathy of undetermined significance [MGUS]/smoldering multiple myeloma [SMM]) to overt MM indicating that there is continuous dissemination/clonal evolution of tumor cells from the original stages of tumor development to the time of clinical presentation. A major challenge in understanding the progression and metastasis of MM is to distinguish alterations driving the tumor growth and evolution from passenger mutations. Genetic screens are powerful tools for assaying phenotypes and identifying causal genes in various hallmarks of cancer progression. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system has emerged as a powerful technology to efficiently and simultaneously perform genome editing of multiple genes. Here we report a genome-wide CRISPR/Cas9-mediated loss of function screen in a xenograft mouse model to investigate the essential drivers of tumor growth and metastasis in MM. Methods: Lentiviral particles from 2 subpools of a human sgRNA library (Avana), each containing 1 sgRNA per gene were introduced into MM1.S (Cas9+/GFP+/Luc+) cell line with the pre-determined amount of virus to achieve 30-50% infection efficiency, corresponding to a multiplicity of infection (MOI) of ~0.5-1. Cells were selected with puromycin for 5-7 days following infection to remove uninfected cells. Selected cells were injected subcutaneously into SCID-Beige mice on both flanks. Genomic DNA from pre-transplantation cells, early primary tumors (~3 weeks post tumor cell injection), late stage primary tumors and metastatic bone marrow samples were extracted. gDNA was amplified following adaptor ligation and barcoding of the samples and PCR products were subsequently sequenced on a HiSeq2000 (Illumina). Results: To investigate the sgRNA library dynamics in different sample types (pre-transplantation cells, early primary tumor, late primary tumor, and bone marrow metastasis), we compared the overall distributions of sgRNAs from all sequenced samples. The early tumor sample replicates of both subpools on average retained 77.3% and 94.7% of the sgRNAs found in the pre-transplanted cell populations, while the late primary tumors retained 59.4% and 65.6% of the sgRNAs respectively, compared to early tumors. Interestingly, only a small fraction of sgRNAs (1.1% and 3.4% of sgRNAs in the pre-transplantation cells, 10.7% and 7.2% of sgRNAs in the late primary tumors for the 2 subpools respectively) were detected in the metastatic bone marrow samples. Using gene set enrichment analysis (GSEA), we found that the gene targets of the most enriched sgRNAs in the bone marrow samples were preferentially involved in important cellular processes, such as cell cycle regulation, protein translation, and several signaling pathways. Additionally we compared sgRNAs present in early primary tumor versus pre-transplantation cells and late primary tumor and found that many sgRNAs were depleted during tumor progression, indicating that their target genes were important for progression. These depleted sgRNAs in both stages mainly targeted genes involved in mTORC1 and DNA repair pathways, many of which are regulated by MYC and cell cycle related targets of E2F transcription factors. Conclusion: We established a platform for future in vivo Cas9 screens using the genome-wide CRISPR screening libraries to explore potential new targets in regulating tumor dissemination, colonization and metastasis in MM. In addition, this in vivo screening could potentially be used to investigate essential genes of response to targeted therapies or/and immunotherapies. Thus, CRISPR/Cas9-based in vivo screening is a powerful tool for functional genomics discoveries. Disclosures Roccaro: Takeda Pharmaceutical Company Limited: Honoraria. Ghobrial:BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria.

scholarly journals Pre-metastatic Niche Formation in Different Organs Induced by Tumor Extracellular Vesicles

2021 ◽  
Vol 9 ◽  
Author(s):  
Qi Dong ◽  
Xue Liu ◽  
Ke Cheng ◽  
Jiahao Sheng ◽  
Jing Kong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Extracellular Vesicles ◽  
Critical Role ◽  
Matrix Remodeling ◽  
Metastatic Niche ◽  
Primary Tumors ◽  
Target Organs ◽  
Bone Marrow Derived Cells ◽  
Metastatic Microenvironment ◽  
Underlying Mechanisms

Primary tumors selectively modify the microenvironment of distant organs such as the lung, liver, brain, bone marrow, and lymph nodes to facilitate metastasis. This supportive metastatic microenvironment in distant organs was termed the pre-metastatic niche (PMN) that is characterized by increased vascular permeability, extracellular matrix remodeling, bone marrow-derived cells recruitment, angiogenesis, and immunosuppression. Extracellular vesicles (EVs) are a group of cell-derived membranous structures that carry various functional molecules. EVs play a critical role in PMN formation by delivering their cargos to recipient cells in target organs. We provide an overview of the characteristics of the PMN in different organs promoted by cancer EVs and the underlying mechanisms in this review.

Platelet Sequestered Proteins Mediate Pre-Metastatic Communication Between Tumors and Bone

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1063-1063
Author(s):  
Bethany A. Kerr ◽  
Tatiana V. Byzova
Keyword(s):  
Bone Formation ◽  
Tumor Growth ◽  
Bone Remodeling ◽  
Primary Tumor ◽  
Conditional Knockout ◽  
Bone Microenvironment ◽  
Tumor Bearing ◽  
Tgf Β1 ◽  
Platelet Depletion

Abstract Tumors can be considered parasites that exploit the host’s resources in order to promote their own growth. Tumors secrete growth factors and cytokines (tumor secretome) which recruit platelets, blood vessels, and bone marrow-derived cells (BMDCs) to promote angiogenesis and tumor progression. We have recently demonstrated that distant tumor growth can stimulate bone formation and BMDC mobilization prior to metastasis. However, the mechanism of communication between the primary tumor and the bone microenvironment remains unknown. Signals from the tumor to the bone microenvironment are likely transmitted through the circulation; nevertheless, these signals need to be protected from degradation or utilization prior to reaching their target. We hypothesized that platelets could function as regulated storage compartments for the tumor secretome. Using a murine platelet depletion model during tumor growth, we assessed the role of platelets in BMDC homing and bone remodeling. We demonstrate that platelet depletion prevents BMDC mobilization and recruitment into tumors. Further, platelet depletion inhibited tumor-induced bone formation. To determine which tumor-derived proteins in platelets were responsible for changes in BMDC mobilization and bone remodeling, we analyzed the tumor secretome components and found that 77% of proteins are enriched within platelets over plasma, and that these proteins regulate BMDC mobilization and bone remodeling. In addition, we discovered that tumor-derived proteins, specifically transforming growth factor (TGF)-β1 and matrix metalloproteinases, sequestered within platelets could stimulate osteoblast differentiation and mineralization in vitro. We also found that thrombospondin (TSP)-1 levels are increased in the platelets of tumor-bearing mice. Finally, we assessed the role of the TSP-1/TGF-β1 signaling axis in tumor-induced bone formation and BMDC mobilization. Tumors in TSP-1 null mice were larger, however tumor-induced bone remodeling decreased. Interestingly, in tumor-bearing mice, high levels of TGF-β1 were being retained in the platelets due to a lack of TSP-1 to activate and release TGF-β1. To examine the role of platelet TGF-β1 in the process of tumor-induced bone remodeling, tumors were implanted in platelet-specific TGF-β1 conditional knockout mice and the changes in tumor size and the bone microenvironment were assessed. In summary, our data show that platelet sequestration and secretion of tumor-derived proteins represent a cellular mechanism mediating communication between the bone microenvironment and the primary tumor. Disclosures: No relevant conflicts of interest to declare.

Abstract 1418: Stromal cells of prostate, not the bone marrow, facilitate prostate cancer osteoblastic tumor growth in bone

2010 ◽  
Author(s):  
Xiaohong Li ◽  
Julie A. Sterling ◽  
Jheelam Banerjee ◽  
Steve Munoz ◽  
Gregory R. Mundy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Stromal Cells

Prostate cancer: Autologous immunotherapy optimized by indoleamine-2,3-dioxygenase (IDO)-inhibitor as immune-tolerance breaker

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12509-12509
Author(s):  
E. M. Lasalvia-Prisco ◽  
E. Garcia-Giralt ◽  
S. Cucchi ◽  
J. Larrañaga ◽  
D. Wagner
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Immune Tolerance ◽  
Performance Status ◽  
Tumor Growth Inhibition ◽  
Primary Tumors ◽  
Group Iii ◽  
Group I ◽  
Group Ii ◽  
Asco Meeting

12509 Background: In several peer review publications (Cancer Biol Ther 2003) our team has reported a procedure of cancer immunotherapy using an autologous thermostable hemoderivative vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors including prostate cancer. Last year (ASCO Meeting 2005) we have reported that the tolerance break for tumor associated antigens through the interference with CD4+CD25+ regulatory cells is a component of the mechanism of action of the ATHV antitumoral effect. Therefore, we have intended to optimize this autologous immunotherapy adding to the procedure different steps of immune-tolerance blockage selected due to their proven efficacy in pre-clinical models and their feasibility in the frame of ATHV technology. In this study we report the results in prostate cancer when the adjuvant step added was the translational knowledge the tolerance blockage by IDO-inhibition through 1-Methyl-Tryptophane or 1-MT (Munn DH et al J Exp Med 1999). Methods: Thirty metastasic prostate cancer patients, hormone and chemotherapy resistant, Performance Status ≤ 2 and PSA progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were randomized in 3 groups submitted to 3 different treatments: I, only sympthomatic; II, the previously reported ATHV and III, ATHV + simultaneous s.c. 1-MT. Tumor size increase (tumor growth) measured according RECIST was registered in each case. Mean difference in the 3 groups was statistically assessed (Student’s t-test). Tryptophane to Kynurenine conversion was tested to assess IDO inhibition. Results: Tumor growth was significantly slower in Group II and III than in Group I (p<0.01 and p<0.005). Tumor growth was also significantly slower in Group III than in Group II (p<0.02). IDO-inhibition was confirmed only in Group III. No relevant toxicities were detected. Conclusions: These results support that additional tolerance break by IDO-inhibition optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. No significant financial relationships to disclose.

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