scholarly journals Tumor cell MT1-MMP is dispensable for osteosarcoma tumor growth, bone degradation and lung metastasis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Signe Z. Ingvarsen ◽  
Henrik Gårdsvoll ◽  
Sander van Putten ◽  
Kirstine S. Nørregaard ◽  
Oliver Krigslund ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
Human Osteosarcoma ◽  
Strong Expression ◽  
Bone Degradation ◽  
Human Osteosarcoma Cells

Abstract The membrane-anchored matrix metalloprotease MT1-MMP is a potent collagenolytic enzyme with a well-established role in extracellular matrix turnover and cellular invasion into collagen-rich tissues. MT1-MMP is highly expressed in various types of cancer and has been demonstrated to be directly involved in several stages of tumor progression, including primary tumor growth, angiogenesis, invasion and metastasis. Osteosarcoma is the most common type of primary bone cancer. This disease is characterized by invasive tumor growth, leading to extensive bone destruction, and metastasis to the lungs. The tumor cells in human osteosarcoma display a strong expression of MT1-MMP, but the role of MT1-MMP in osteosarcoma progression is currently unknown. In this study, we investigated the role of MT1-MMP during various stages of osteosarcoma development. We utilized an optimized orthotopic murine osteosarcoma model and human osteosarcoma cells in which the MT1-MMP gene was knocked out using CRISPR/Cas9. We observed a strong expression of MT1-MMP in wildtype cells of both primary tumors and lung metastases, but, surprisingly, MT1-MMP deficiency did not affect primary tumor growth, bone degradation or the formation and growth of lung metastases. We therefore propose that, unlike findings reported in other cancers, tumor-expressed MT1-MMP is dispensable for all stages of osteosarcoma progression.

Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis

2007 ◽  
Vol 26 (3-4) ◽  
pp. 611-621 ◽  
Author(s):  
Hendrik Seeliger ◽  
Markus Guba ◽  
Axel Kleespies ◽  
Karl-Walter Jauch ◽  
Christiane J. Bruns
Keyword(s):  
Tumor Growth ◽  
Solid Tumor ◽  
Primary Tumor ◽  
Primary Tumor Growth

scholarly journals Host deficiency in ephrin-A1 inhibits breast cancer metastasis

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 217 ◽  
Author(s):  
Eileen Shiuan ◽  
Ashwin Inala ◽  
Shan Wang ◽  
Wenqiang Song ◽  
Victoria Youngblood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Primary Tumor ◽  
Tumor Recurrence ◽  
Cancer Metastasis ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
4T1 Cells

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

Melatonin decreases metastasis, primary tumor growth and angiogenesis in a mice model of breast cancer

2021 ◽  
pp. 096032712110028
Author(s):  
Asiye Kubra Karadas ◽  
Sayra Dilmac ◽  
Gunes Aytac ◽  
Gamze Tanriover
Keyword(s):  
Liver Metastasis ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Inflammatory Responses ◽  
Control Group ◽  
Primary Tumor Growth ◽  
Mice Model ◽  
Primary Tumors ◽  
Tumor Group ◽  
Pre Treatment

The goal of this study was to mechanistically analyze the effects of pre-treatment or post-treatment melatonin on the metastatic spread in a mice model. Consequently, the effects on the tumor growth, angiogenesis and metastasis were evaluated with immunohistochemical and western blot analysis. 8–10 weeks-old female BALB/c mice (n = 60, 10/group) were used. Liver metastatic cells (4TLM) from 4T1 murine breast carcinoma were previously isolated. Melatonin was administrated either before or after the injection of 4TLM cells into the mammary pad. Tumor and vehicle (%6 ethanol) injections were given to vehicle groups. Tumor group consisted of the mice injected with only 4TLM cells injected to tumor group and no intervention to control group. Necropsies were performed 27 days after injection of 4TLM. Primary tumors and metastatic tissues were removed. Furthermore, changes in lung and liver metastasis and primary tumor growth and angiogenesis were evaluated. In our study neutrophil levels were noted to be increased in peripheral blood of the tumor-bearing mice. Melatonin exerted inhibitory effects on the 4TLM-induced leukocytosis. Melatonin significantly decreased lung and liver metastasis, primary tumor growth and angiogenesis. The results demonstrated that melatonin might have a therapeutic role through reducing systemic inflammatory responses, metastasis, tumor growth and angiogenesis.

scholarly journals Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261633
Author(s):  
Jeremy G. T. Wurtzel ◽  
Sophia Lazar ◽  
Sonali Sikder ◽  
Kathy Q. Cai ◽  
Igor Astsaturov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Primary Tumor ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
Solid Tumor Growth

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles—which were depleted of platelet-enriched miRNAs—demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways–notably pathways related to epithelial-mesenchymal transition—in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.

A novel role for 17-Β estradiol and testosterone in osteosarcoma tumorigenesis and metastasis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23012-e23012
Author(s):  
Jake N. Lichterman ◽  
Robert Post ◽  
Luke Menken ◽  
Bishoy Saad ◽  
Justin Delgado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Primary Tumor ◽  
Luciferase Expression ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Primary Tumor Growth ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cell ◽  
Proliferation And Invasion

e23012 Background: Pulmonary metastases still remains the leading cause of mortality in osteosarcoma, with a 5-year survival rate of less than 30%. 17-β estradiol and testosterone are known to promote tumorigenesis and metastasis in other cancers, but its role in osteosarcoma tumorigenesis and metastasis is unclear. An understanding of the mechanism that these hormones have in osteosarcoma tumorigenesis and metastasis will lead to new therapeutic strategies using currently available targeted therapies used in breast and prostate cancer. Methods: We began by assessing the in vitro characteristics of two human osteosarcoma cell lines treated with 17-β estradiol or testosterone via proliferation and invasion assays. For the in vivo experiments, NCR nu/nu mice were injected with two luciferase-tagged human osteosarcoma cell lines and treated with 17-β estradiol and testosterone slow-release pellets. We first injected the mice subcutaneously and monitored tumor growth via caliper measurements. In the second experiment we injected the cell lines intratibially and monitored primary tumor growth in the bone and monitored metastasis formation in the lungs via IVIS bioluminescent imaging. Quantification of luciferase signal (photons/second) in the lungs was performed via the Xenogen Living Image software. H&E and immunohistochemistry for luciferase expression was performed on lung tissue to quantify tumor burden in the lungs. Statistical analysis was performed using Graphpad Prism. Results: Treatment with 17-β estradiol and testosterone increased cell proliferation and invasion in a dose-dependent manner. We observed increased tumor growth with both 17-β estradiol and testosterone in the subcutaneous model. In the intratibial experiment, testosterone increases primary tumor growth, but has no effect on metastasis. 17-β estradiol decreases primary tumor growth, but increases metastasis in a cell line independent manner. Conclusions: This study demonstrates a novel role for the puberty-related sex steroid hormones, 17-β estradiol and testosterone, in osteosarcoma tumor growth and metastasis. Uncovering the mechanism behind this phenomenon will uncover new therapeutic options for this devastating disease.

The Role of Macrophages in the Regulation of Primary Tumor Growth

Pathobiology ◽  
1991 ◽  
Vol 59 (4) ◽  
pp. 239-242 ◽  
Author(s):  
Sabine Walter ◽  
Deanna Govoni ◽  
Barbara Bottazzi ◽  
Alberto Mantovani
Keyword(s):  
Tumor Growth ◽  
Primary Tumor ◽  
Primary Tumor Growth

Altered CXCL12 expression reveals a dual role of CXCR4 in osteosarcoma primary tumor growth and metastasis

2016 ◽  
Vol 142 (8) ◽  
pp. 1739-1750 ◽  
Author(s):  
Olga Neklyudova ◽  
Matthias J. E. Arlt ◽  
Patrick Brennecke ◽  
Marcus Thelen ◽  
Ana Gvozdenovic ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Primary Tumor ◽  
Dual Role ◽  
Primary Tumor Growth ◽  
Cxcl12 Expression ◽  
Tumor Growth And Metastasis

scholarly journals Host deficiency in ephrin-A1 inhibits breast cancer metastasis

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 217
Author(s):  
Eileen Shiuan ◽  
Ashwin Inala ◽  
Shan Wang ◽  
Wenqiang Song ◽  
Victoria Youngblood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Primary Tumor ◽  
Tumor Recurrence ◽  
Cancer Metastasis ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
4T1 Cells

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

scholarly journals Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo.

1988 ◽  
Vol 8 (8) ◽  
pp. 3143-3149 ◽  
Author(s):  
B Korczak ◽  
I B Robson ◽  
C Lamarche ◽  
A Bernstein ◽  
R S Kerbel
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Mammary Adenocarcinoma ◽  
Cell Populations ◽  
Primary Tumors ◽  
Large Numbers ◽  
Retrovirus Vector

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

scholarly journals Crucial Role of the YAP/TEAD Axis in Osteosarcoma Tumor Growth: Effects of YAP Inhibitors Verteporfin and CA3 on Tumor Growth in vivo

2020 ◽  
Author(s):  
Sarah Morice ◽  
Mathilde Mullard ◽  
Regis Brion ◽  
Maryne Dupuy ◽  
Sarah Renault ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Survival Rates ◽  
Osteosarcoma Cell ◽  
Primary Tumor Growth ◽  
Cellular Analysis ◽  
Kaplan Meier

Abstract BackgroundOsteosarcoma is the first primary bone tumor in children and adolescents. Despite progress in the understanding of the biology of these tumors, survival rates have progressed very little in recent decades. In this context, although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use of inhibitors in a preclinical model must be demonstrated.MethodsThe identification of a YAP signature was carried out by RNAseq analysis from a cohort of patients. Survival rates were assessed by Kaplan-Meier assays. The role of TEAD in the control of osteosarcoma cell proliferation by YAP has been realized by various molecular and cellular biology approaches (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) using overexpression of mutated forms of YAP able or unable to interact with TEAD. The role of TEAD in YAP regulation of primary tumor growth, and the effects of YAP inhibitors in vivo were realized using an orthotopic model of osteosarcoma. ResultsRNA-seq analysis and Kaplan-Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients outcome. Molecular and cellular analysis using overexpression of mutated forms of YAP able or unable to interact with TEAD, indicate that TEAD is crucial for YAP-driven cell proliferation and in vivo tumor growth. In addition, in vivo experiments show that two YAP/TEAD inhibitors, verteporfin and CA3, reduce primary tumor growth. In this context, in vitro experiments demonstrate that these inhibitors decrease YAP expression, YAP/TEAD transcriptional activity and cell viability mainly by their ability to induce cell apoptosis.ConclusionWe thus demonstrate that the YAP/TEAD signaling axis is a central actor in mediating primary tumor growth of osteosarcoma, and that the use of YAP inhibitors may be a promising therapeutic strategy against osteosarcoma tumor growth.

Sign in / Sign up

Export Citation Format

Share Document