Embedding similarities between embryos and circulating tumor cells: fundamentals of abortifacients used for cancer metastasis chemoprevention

Abstract Background The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion. Methods Biomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17β-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined. Results Both embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17β-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMPs. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice. Conclusions The similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present studies offer the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.

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Embedding Similarities Between Embryos And Circulating Tumor Cells: Fundamentals of Abortifacients Used For Cancer Metastasis Chemoprevention

10.21203/rs.3.rs-779124/v1 ◽

2021 ◽

Author(s):

Jie Wang ◽

Xiaobo Yu ◽

Huayi Peng ◽

Yusheng Lu ◽

Shuhui Li ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Cell ◽

Cancer Metastasis ◽

Embryo Implantation ◽

Migration And Invasion ◽

Female Mice ◽

Cancer Metastases ◽

17Β Estradiol ◽

Mcf 7

Abstract Background: The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion.Methods: Biomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17β-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined. Results: Both embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17β-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMP. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice.Conclusions: The similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present study offers the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.

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Mitotic arrest affects clustering of tumor cells

10.21203/rs.3.rs-47408/v3 ◽

2021 ◽

Author(s):

Julia Bonnet ◽

Lise Rigal ◽

Odile Mondesert ◽

Renaud Morin ◽

Gaelle Corsaut ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Cell ◽

Cell Aggregation ◽

Metastatic Potential ◽

Mitotic Arrest ◽

Chemotherapeutic Agents ◽

The Impact ◽

Mcf 7

Abstract Background Cancer cell aggregation is a key process involved in the formation of tumor cell clusters. It has recently been shown that clusters of circulating tumor cells (CTCs) have an increased metastatic potential compared to isolated circulating tumor cells. Several widely used chemotherapeutic agents that target the cytoskeleton microtubules and cause cell cycle arrest at mitosis have been reported to modulate CTC number or the size of CTC clusters. Results In this study, we investigated in vitro the impact of mitotic arrest on the ability of breast tumor cells to form clusters. By using live imaging and quantitative image analysis, we found that MCF-7 cancer cell aggregation is compromised upon incubation with paclitaxel or vinorelbine, two chemotherapeutic drugs that target microtubules. In line with these results, we observed that MCF-7 breast cancer cells experimentally synchronized and blocked in metaphase aggregated poorly and formed loose clusters. To monitor clustering at the single-cell scale, we next developed and validated an in vitro assay based on live video-microscopy and custom-designed micro-devices. The study of cluster formation from MCF-7 cells that express the fluorescent marker LifeAct-mCherry using this new assay allowed showing that substrate anchorage-independent clustering of MCF-7 cells was associated with the formation of actin-dependent highly dynamic cell protrusions. Metaphase-synchronized and blocked cells did not display such protrusions, and formed very loose clusters that failed to compact. Conclusions Altogether, our results suggest that mitotic arrest induced by microtubule-targeting anticancer drugs prevents cancer cell clustering and therefore, could reduce the metastatic potential of circulating tumor cells.

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Mitotic arrest affects clustering of tumor cells

Cell Division ◽

10.1186/s13008-021-00070-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Julia Bonnet ◽

Lise Rigal ◽

Odile Mondesert ◽

Renaud Morin ◽

Gaëlle Corsaut ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Cell ◽

Cell Aggregation ◽

Metastatic Potential ◽

Mitotic Arrest ◽

Vitro Assay ◽

The Impact ◽

Mcf 7

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Mitotic arrest affects clustering of tumor cells

10.21203/rs.3.rs-47408/v1 ◽

2020 ◽

Author(s):

Julia Bonnet ◽

Lise Rigal ◽

Odile Mondesert ◽

Renaud Morin ◽

Gaelle Corsaut ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Cell ◽

Cell Aggregation ◽

Metastatic Potential ◽

Mitotic Arrest ◽

Vitro Assay ◽

The Impact ◽

Mcf 7

Abstract BackgroundCancer cell aggregation is a key process involved in the formation of tumor cells clusters. It has recently been shown that clusters of circulating tumor cells (CTCs) have an increased metastatic potential compared to isolated circulating tumor cells. Several widely used chemotherapeutic agents that target the cytoskeleton microtubules and cause cell cycle arrest at mitosis have been reported to modulate the number of CTCs or the size of CTC clusters.ResultsIn this study, we investigated in vitro the impact of mitotic arrest on the ability of breast tumor cells to form clusters. By using live imaging and quantitative image analysis, we found that MCF-7 cancer cell aggregation is compromised upon incubation with paclitaxel or vinorelbine, two chemotherapeutic drugs that target microtubules. In line with these results, we found that MCF-7 breast cancer cells experimentally synchronized and blocked in metaphase aggregated poorly with strongly reduced cohesion. To monitor clustering at the single-cell scale, we next developed and validated an in vitro assay based on live video-microscopy and custom-designed micro-devices. The study of cluster formation from MCF-7 cells that express the fluorescent marker LifeAct-mCherry using this new assay allowed showing that substrate anchorage-independent clustering of MCF-7 cells was associated with the formation of actin-dependent highly dynamic cell protrusions. Metaphase-synchronized and blocked cells did not display such protrusions, and formed very loose clusters that failed to compact.ConclusionsAltogether, our results suggest that mitotic arrest induced by microtubule-targeting anticancer drugs prevents cancer cell clustering and therefore, could reduce the metastatic potential of circulating tumor cells.

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Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway

Cell Communication and Signaling ◽

10.1186/s12964-019-0464-x ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Xiao-xiao Zuo ◽

Ya Yang ◽

Yue Zhang ◽

Zhi-gang Zhang ◽

Xiao-fei Wang ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Metastasis ◽

Direct Interaction ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Tgf Β1 ◽

Mcf 7

Abstract Background Integrin-mediated platelet-tumor cell contacting plays an important role in promoting epithelial-mesenchymal transition (EMT) transformation of tumor cells and cancer metastasis, but whether it occurs in breast cancer cells is not completely clear. Objective The purpose of this study was to investigate the role of integrin α2β1 in platelet contacting to human breast cancer cell line MCF-7 and its effect on the EMT and the invasion of MCF-7 cells. Methods Human platelets were activated by thrombin, and separated into pellets and releasates before the co-incubation with MCF-7 cells. Cell invasion was evaluated by transwell assay. The surface integrins on pellets and MCF-7 cells were inhibited by antibodies. The effect of integrin α2β1 on Wnt-β-catenin pathway was assessed by integrin α2β1-silencing and Wnt-β-catenin inhibitor XAV. The therapeutic effect of integrin α2β1-silencing was confirmed in the xenograft mouse model. Results Pellets promote the invasion and EMT of MCF-7 cells via direct contacting of surface integrin α2β1. The integrin α2β1 contacting activates Wnt-β-catenin pathway and promotes the expression of EMT proteins in MCF-7 cells. The activated Wnt-β-catenin pathway also promotes the autocrine of TGF-β1 in MCF-7 cells. Both Wnt-β-catenin and TGF-β1/pSmad3 pathways promote the expression of EMT proteins. Integrin α2β1-silencing inhibits breast cancer metastasis in vivo. Conclusions The direct interaction between platelets and tumor cells exerts its pro-metastatic function via surface integrin α2β1 contacting and Wnt-β-catenin activation. Integrin α2β1-silencing has the potential effect of inhibiting breast cancer metastasis.

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Mitotic arrest affects clustering of tumor cells

10.21203/rs.3.rs-47408/v2 ◽

2020 ◽

Author(s):

Julia Bonnet ◽

Lise Rigal ◽

Odile Mondesert ◽

Renaud Morin ◽

Gaelle Corsaut ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Cell ◽

Cell Aggregation ◽

Metastatic Potential ◽

Mitotic Arrest ◽

Chemotherapeutic Agents ◽

The Impact ◽

Mcf 7

Abstract BackgroundCancer cell aggregation is a key process involved in the formation of tumor cell clusters. It has recently been shown that clusters of circulating tumor cells (CTCs) have an increased metastatic potential compared to isolated circulating tumor cells. Several widely used chemotherapeutic agents that target the cytoskeleton microtubules and cause cell cycle arrest at mitosis have been reported to modulate CTC number or the size of CTC clusters.ResultsIn this study, we investigated in vitro the impact of mitotic arrest on the ability of breast tumor cells to form clusters. By using live imaging and quantitative image analysis, we found that MCF-7 cancer cell aggregation is compromised upon incubation with paclitaxel or vinorelbine, two chemotherapeutic drugs that target microtubules. In line with these results, we observed that MCF-7 breast cancer cells experimentally synchronized and blocked in metaphase aggregated poorly and formed loose clusters. To monitor clustering at the single-cell scale, we next developed and validated an in vitro assay based on live video-microscopy and custom-designed micro-devices. The study of cluster formation from MCF-7 cells that express the fluorescent marker LifeAct-mCherry using this new assay allowed showing that substrate anchorage-independent clustering of MCF-7 cells was associated with the formation of actin-dependent highly dynamic cell protrusions. Metaphase-synchronized and blocked cells did not display such protrusions, and formed very loose clusters that failed to compact.ConclusionsAltogether, our results suggest that mitotic arrest induced by microtubule-targeting anticancer drugs prevents cancer cell clustering and therefore, could reduce the metastatic potential of circulating tumor cells.

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CIRCULATING TUMOR CELLS: WHERE WE LEFT OFF?

Biotechnologia Acta ◽

10.15407/biotech14.04.005 ◽

2021 ◽

Vol 14 (4) ◽

pp. 5-27

Author(s):

I. Kryvoshlyk ◽

Keyword(s):

Cancer Treatment ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Current Knowledge ◽

Treatment Strategies ◽

Current Data ◽

Cancer Prognosis ◽

Migration And Invasion ◽

Tumor Resistance

Cancer metastasis and recurrence are the leading causes of cancer-related death. Tumor cells which leave the primary or secondary tumors and shed into the bloodstream are called circulating tumor cells (CTC). These cells are the key drivers of cancer dissemination to surrounding tissues and to distant organs. The use of CTC in clinical practice necessitates the deep insight into their biology, as well as into their role in cancer evasion of immune surveillance, tumor resistance to chemo- radio- and immunotherapies and metastatic dormancy. Aim. The purpose of the work was to review the current knowledge on the CTC biology, as well as the prospects for their use for the diagnosis and targeted treatment of metastatic disease. Methods. The work proposed the integrative literature review using MEDLINE, Biological Abstracts and EMBASE databases. Results. This review summarizes and discusses historical milestones and current data concerning СTС biology, the main stages of their life cycle, their role in metastatic cascade, clinical prospects for their use as markers for the diagnosis and prognostication of the disease course, as well as targets for cancer treatment. Conclusions. Significant progress in the area of CTC biology and their use in cancer theranostics convincingly proved the attractiveness of these cells as targets for cancer prognosis and therapy. The effective use of liquid biopsy with quantitative and phenotypic characteristics of CTCs is impeded by the imperfection of the methodology for taking biological material and by the lack of reliable markers for assessing the metastatic potential of CTCs of various origins. The variety of mechanisms of tumor cells migration and invasion requires the development of complex therapeutic approaches for anti-metastatic therapy targeting CTCs. Efforts to address these key issues could help developing new and effective cancer treatment strategies.

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FlowCell-enriched circulating tumor cells as a predictor of lung cancer metastasis

Human Cell ◽

10.1007/s13577-021-00500-8 ◽

2021 ◽

Author(s):

Yan Lu ◽

Yushuang Zheng ◽

Yuhong Wang ◽

Dongmei Gu ◽

Jun Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Cancer Metastasis ◽

Lung Tumor ◽

Early Stage ◽

High Rate ◽

Early Stage Lung Cancer ◽

Lung Cancer Metastasis ◽

Number Of Patients

AbstractLung cancer is the most fetal malignancy due to the high rate of metastasis and recurrence after treatment. A considerable number of patients with early-stage lung cancer relapse due to overlooked distant metastasis. Circulating tumor cells (CTCs) are tumor cells in blood circulation that originated from primary or metastatic sites, and it has been shown that CTCs are critical for metastasis and prognosis in various type of cancers. Here, we employed novel method to capture, isolate and classify CTC with FlowCell system and analyzed the CTCs from a cohort of 302 individuals. Our results illustrated that FlowCell-enriched CTCs effectively differentiated benign and malignant lung tumor and the total CTC counts increased as the tumor developed. More importantly, we showed that CTCs displayed superior sensitivity and specificity to predict lung cancer metastasis in comparison to conventional circulating biomarkers. Taken together, our data suggested CTCs can be used to assist the diagnosis of lung cancer as well as predict lung cancer metastasis. These findings provide an alternative means to screen early-stage metastasis.

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The Role of Protein Arginine Methyltransferase 1 in Gastrointestinal Cancers

10.5772/intechopen.96197 ◽

2021 ◽

Author(s):

Jin Zou ◽

Wei Shen ◽

Yu Zhang ◽

Shibo Ying

Keyword(s):

Tumor Cells ◽

Cancer Progression ◽

Cancer Metastasis ◽

Arginine Methylation ◽

Gastrointestinal Tumors ◽

Migration And Invasion ◽

Arginine Methyltransferase ◽

Tumorigenic Mechanism ◽

Methyltransferase 1

Mammals can produce nine kinds of arginine methylation enzymes that can be divided into three types (I, II, and III) according to their catalytic activity. Arginine methyltransferase 1 (PRMT1), as the first discovered arginine methyltransferase type I, has been reported to be involved in cell signal transduction, DNA damage repair, RNA transcription and other processes. Its imbalance or abnormal expression is also involved in cancer metastasis. PRMT1 is highly expressed in gastrointestinal tumors and promotes tumor biomarkers expression, chemotherapy resistance and tumorigenicity to promote cancer progression, while downregulation of PRMT1 expression can inhibit the migration and invasion of related tumor cells or promote tumor cells apoptosis and inhibit the progression of cancer. Therefore, PRMT1 may be a cancer therapeutic target. In this paper, arginine methylase 1 expression in various types of gastrointestinal tumors, the tumorigenic mechanism and the role of PRMT1 in tumorigenesis and development were reviewed.

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Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades

Cancers ◽

10.3390/cancers11060813 ◽

2019 ◽

Vol 11 (6) ◽

pp. 813 ◽

Cited By ~ 18

Author(s):

Michelle K. Y. Siu ◽

Yu-Xin Jiang ◽

Jing-Jing Wang ◽

Thomas H. Y. Leung ◽

Chae Young Han ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Cancer Cell ◽

Cancer Metastasis ◽

Ovarian Cancer Cell ◽

Lactate Production ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Hexokinase 2 ◽

Cell Migration And Invasion

Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.

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