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 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.

Effect of general anesthetics on the tumor micro-environment in mouse models of breast cancers of spontaneous metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15503-e15503
Author(s):  
Jun Lin ◽  
Ru Li ◽  
Yujie Huang
Keyword(s):  
Breast Cancer ◽  
Mouse Models ◽  
Lung Metastasis ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Health Concern ◽  
Breast Cancers ◽  
General Anesthetics ◽  
Primary Tumors

e15503 Background: Metastatic breast cancer is a pressing health concern worldwide. Various treatments have been developed but no significant long-term changes in overall survival are observed. Therefore, there is a demand to improve current therapies to treat this disease. Surgical resection of the primary tumors is essential in the treatment. However, accumulating evidence alludes to a role for volatile anesthetics which are used during the surgery in metastatic tumor development, but the mechanism remains largely unknown. We have shown anesthetics exert different effects on lung metastasis in mouse models of breast cancers. This study analyses the effect of general anesthetics in lung microenvironment associated with the increased metastases. Methods: Balb/c mice and NOD-SCID mice were orthotopically implanted with 4T1 cells and MDA-MB-231 cells respectively, in the mammary fat pad to generate primary tumors. Mice were subjected to the tested anesthetic during implantation and/or before and after surgery. Surgical dissection of primary tumor was performed under anesthesia with sevoflurane or an intravenous anesthetic propofol. Survival curve was constructed and analysed. Mice were euthanized to harvest tissues for histology and cell analysis. Results: As we previously reported, surgical dissection of primary tumor in mice under anesthesia with sevoflurane led to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane was associated with increased IL6(Li, Huang, & Lin, 2020). Here we show that anesthesia with sevoflurane resulted in changes of stroma composition in the lung, which was reversed by IL6 pathway interruption. Conclusions: Those results contribute to our understanding of effects of sevoflurane on cancer metastasis and suggest a potential therapeutic approach to overcome the risk of general anesthesia. Li, R., Huang, Y., & Lin, J. (2020). Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models. Nat Commun, 11, 642.

scholarly journals Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer

2019 ◽  
Vol 20 (24) ◽  
pp. 6342
Author(s):  
Teizo Yoshimura ◽  
Kaoru Nakamura ◽  
Chunning Li ◽  
Masayoshi Fujisawa ◽  
Tsuyoshi Shiina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Cancer Progression ◽  
Critical Role ◽  
Gm Csf ◽  
4T1 Cells

We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

scholarly journals Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth

Oncogene ◽  
2016 ◽  
Vol 35 (46) ◽  
pp. 5977-5988 ◽  
Author(s):  
S J Werden ◽  
N Sphyris ◽  
T R Sarkar ◽  
A N Paranjape ◽  
A M LaBaff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Primary Tumor Growth

Clinical and pathologic characteristics of patients with breast cancer and a second non-breast primary tumor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11539-e11539
Author(s):  
Gul Atalay Basaran ◽  
Aziz Yazar ◽  
Cihan Uras ◽  
Evrim Tezcanli ◽  
Devrim Cabuk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Primary Tumor ◽  
Breast Tumor ◽  
Cancer Metastasis ◽  
Histological Grade ◽  
Breast Tumors ◽  
Second Primary ◽  
Primary Tumors ◽  
Second Primary Tumors

e11539 Background: We aimed to investigate the clinical and pathologic characteristics of patients with breast cancer (BC) who had a non-breast primary tumor and treated in our hospital. Methods: We identified BC patients with a second non-breast primary tumor retrospectively in our database. The tumors arising in a sequence by less than 2 months are accepted as synchronous malignancies. We noted clinical and pathological characteristics of breast tumors and analyzed the relapse patterns, the frequency and type of second non-breast primary tumors. Results: A total of 48 patients were identified. Median age was 59 years old. Thirty-four patients were postmenopausal, 41 tumors were IDC, 2 were DCIS only, eight were multiffocal. Two patients had metastatic BC at the time of diagnosis. Ninety-three (n: 26) % patients had breast conserving surgery, 2 had bilateral BC. Twenty-eight patients had node negative disease, 12 had node positive disease and 2 had micrometatatic nodal involvement. Fifty-four % were T1, 31% were T2 tumors. Histological grade was 3 for 14, 2 for 15 and 1 for 7 breast tumors. Forty patients had ER positive disease, 4 had ER/ PR negative disease, 2 tumors were triple negative and 6 tumors were Her-2 positive. Among non-breast second primary tumors; 29 arose after, 11 arose before the diagnosis of BC and 8 arose synchronously with BC. The most common non-breast second primary tumors were as follows: 15% lung cancer, 20% colorectal cancers, 13% ovarian cancer, 10% thyroid cancer, and 8% lymphoma/leukemia. With a median follow up of 76 months, there were 6 relapses; 4 of them were BC relapses. Among these 4 BC relapses, 3 patients had brain metastases and one patient had bone metastasis. There were 4 deaths; 2 were due to BC metastases, one was due to rectal cancer metastasis and the other was due to relapse of sarcoma. Conclusions: Most breast tumors were at early stage and were hormone sensitive. The most common second non-breast primary tumors arising after diagnosis of BC were colorectal, thyroid and lung cancers. The most common second non-breast tumor arising synchronously with BC was lung cancer and the most common second non-breast tumor arising before diagnosis of BC was lymphoma/leukemia.

scholarly journals SOX4 promotes the growth and metastasis of breast cancer

2020 ◽  
Author(s):  
Jing Zhang ◽  
Chunhua Xiao ◽  
Zhenbo Feng ◽  
Yun Gong ◽  
Baohua Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Lymph Nodes ◽  
Cell Viability ◽  
Cancer Cell ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Primary Tumors

Abstract Purpose Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo . Methods We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. Results SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo . It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. Conclusions SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

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.

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