Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

Yin, Mingzhu; Li, Xia; Tan, Sue Yee; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge; Wang, Min

doi:10.1172/jci87252

Cited by 324 publications

(330 citation statements)

References 54 publications

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“…Spheroid-associated myoibroblasts may also secrete factors within the microenvironment of the spheroids that induce signaling events in tumor cells to further inhibit anoikis. Recent data suggest that tumor-associated macrophages (TAMs) may promote spheroid formation and tumor growth in a mouse model [51]. This group found that nearly 80% of macrophages iniltrated in the peritoneal cavity were detected in spheroids.…”

Section: Cellular Contents: Contribution To Eoc Metastasismentioning

confidence: 99%

“…This group found that nearly 80% of macrophages iniltrated in the peritoneal cavity were detected in spheroids. Spheroid-associated TAMs were shown to secrete large amounts of epidermal growth factor (EGF), which leads to upregulation of integrin and ICAM-1 expression in tumor cells to form a positive autocrine feedback loop [51].…”

Section: Cellular Contents: Contribution To Eoc Metastasismentioning

confidence: 99%

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Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

Matte¹,

Bessette²,

Piché³

2017

Ascites - Physiopathology, Treatment, Complications and Prognosis

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Until recently, ovarian cancer research has mainly focused on the tumor cell themselves ignoring for the most part the surrounding tumor environment. However, one of the major conceptual advances in oncology over the last few years has been the appreciation that major aspects of cancer biology are inluenced by the tumor environment. Malignant ascites accumulates in the peritoneal cavity during ovarian cancer progression and constitutes a unique pro-inlammatory tumor environment providing a framework that orchestrates cellular and molecular changes contributing to aggressiveness and disease progression. The composition of ascites, which includes cellular and acellular components, constantly adapts during the course of the disease in response to various cellular cues originating from both tumor and stromal cells. Increasing evidence now supports an active role of ascites in the progression of ovarian cancer. Although much work is still needed to fully understand the contribution of ascites to ovarian cancer aggressiveness, this tumor environment potentially provides a wealth of opportunities for translational research including biomarker discovery and novel therapeutic target identiication. In this review, we discuss recent advances in our understanding of ascites pathophysiology, the characterization of its cellular and acellular contents, the intercellular crosstalks, and how these data can be used to improve the outcome of ovarian cancer.

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Section: Cellular Contents: Contribution To Eoc Metastasismentioning

confidence: 99%

Section: Cellular Contents: Contribution To Eoc Metastasismentioning

confidence: 99%

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

Matte¹,

Bessette²,

Piché³

2017

Ascites - Physiopathology, Treatment, Complications and Prognosis

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“…In an in vitro model of EMT, it was shown that M2-type macrophages in direct contact with carcinoma cells facilitated the dispersion of the latter via ICAM-1 and integrin CD18 interaction [26]. Similarly, in a mouse ovarian cancer model, the initial steps of spheroid formation and transcoelomic metastasis were facilitated by the attachment of cancer cells to macrophages via CD11b/CD18 -ICAM-1 adhesion [25]. If binding to ICAM-1 was neutralized with antibodies, spheroid formation and ovarian cancer progression were impaired [25].…”

Section: Lfa-1 Participates In the Cytotoxic Immune Response Against mentioning

confidence: 98%

“…These tumorassociated macrophages contribute to the epithelial-mesenchymal transition (EMT) and tumor dissemination [22] [23] [24] [25]. The metastasis-promoting effect of macrophages is exerted through cytokine secretion such as TGFß [23].…”

Section: Lfa-1 Participates In the Cytotoxic Immune Response Against mentioning

confidence: 99%

“…Similarly, in a mouse ovarian cancer model, the initial steps of spheroid formation and transcoelomic metastasis were facilitated by the attachment of cancer cells to macrophages via CD11b/CD18 -ICAM-1 adhesion [25]. If binding to ICAM-1 was neutralized with antibodies, spheroid formation and ovarian cancer progression were impaired [25].…”

Section: Lfa-1 Participates In the Cytotoxic Immune Response Against mentioning

confidence: 99%

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Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

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The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

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Molecular characteristics and tumorigenicity of ascites‐derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer

et al. 2021

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Ovarian cancer disseminates primarily intraperitoneally. Detached tumor cell aggregates (spheroids) from the primary tumor are regarded as ‘metastatic units’ that exhibit a low sensitivity to classical chemotherapy, probably due to their unique molecular characteristics. We have analyzed the cellular composition of ascites from OvCa patients, using flow cytometry, and studied their behavior in vitro and in vivo . We conclude that ascites‐derived cultured cells from OvCa patients give rise to two subpopulations: adherent cells and non‐adherent cells. Here, we found that the AD population includes mainly CD90 + cells with highly proliferative rates in vitro but no tumorigenic potential in vivo , whereas the NAD population contains principally tumor cell spheroids (EpCAM + /CD24 + ) with low proliferative potential in vitro . Enriched tumor cell spheroids from the ascites of high‐grade serous OvCA patients, obtained using cell strainers, were highly tumorigenic in vivo and their metastatic spread pattern precisely resembled the tumor dissemination pattern found in the corresponding patients. Comparative transcriptome analyses from ascites‐derived tumor cell spheroids ( n = 10) versus tumor samples from different metastatic sites ( n = 30) revealed upregulation of genes involved in chemoresistance ( TGM1 , HSPAs, MT1s), cell adhesion and cell‐barrier integrity ( PKP3 , CLDNs, PPL ), and the oxidative phosphorylation process. Mitochondrial markers (mass and membrane potential) showed a reduced mitochondrial function in tumoroids from tumor tissue compared with ascites‐derived tumor spheroids in flow cytometry analysis. Interestingly, response to OXPHOS inhibition by metformin and IACS010759 in tumor spheroids correlated with the extent of mitochondrial membrane potential measured by fluorescence‐activated cell sorting. Our data contribute to a better understanding of the biology of ovarian cancer spheroids and identify the OXPHOS pathway as new potential treatment option in advanced ovarian cancer.

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Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

Cited by 324 publications

References 54 publications

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies

Role of LFA-1 and ICAM-1 in Cancer

Molecular characteristics and tumorigenicity of ascites‐derived tumor cells: mitochondrial oxidative phosphorylation as a novel therapy target in ovarian cancer

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