scholarly journals Metastatic tumor cells exploit their adhesion repertoire to counteract shear forces during intravascular arrest

2018 ◽  
Author(s):  
Naël Osmani ◽  
Gautier Follain ◽  
Marìa Jesùs Garcia Leòn ◽  
Olivier Lefebvre ◽  
Ignacio Busnelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Integrin Αvβ3 ◽  
Metastatic Tumor ◽  
Shear Forces ◽  
Integrin Α5β1 ◽  
Lower Shear ◽  
Cell Adhesive

SUMMARYCancer metastasis is a process whereby a primary tumor spreads to distant organs. We have previously demonstrated that blood flow controls the intravascular arrest of circulating tumor cells (CTCs), through stable adhesion to endothelial cells. We now aim at defining the contribution of cell adhesive potential and at identifying adhesion receptors at play. Early arrest is mediated by the formation of weak adhesion depending on CD44 and integrin αvβ3. Stabilization of this arrest uses integrin α5β1-dependent adhesions with higher adhesion strength, which allows CTCs to stop in vascular regions with lower shear forces. Moreover, blood flow favors luminal deposition of fibronectin on endothelial cells, an integrin α5β1 ligand. Finally, we show that only receptors involved in stable adhesion are required for subsequent extravasation and metastasis. In conclusion, we identified the molecular partners that are sequentially exploited by CTCs to arrest and extravasate in vascular regions with permissive flow regimes.

scholarly journals RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Tsung-Lin Cheng ◽  
Chao-Han Lai ◽  
Shinn-Jong Jiang ◽  
Jui-Hsiang Hung ◽  
Shi-Kai Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Caspase 3 ◽  
Growth Factor Receptor ◽  
Metastatic Tumor ◽  
Anoikis Resistance ◽  
Rhomboid Protease ◽  
Egfr Activation ◽  
Kinase Phosphorylation

Anoikis resistance allows metastatic tumor cells to survive in a homeless environment. Activation of epithelial growth factor receptor (EGFR) signaling is one of the key mechanisms for metastatic tumor cells to resist anoikis, yet the regulation mechanisms of homeless-triggered EGFR activation in metastatic tumor cells remain unclear. Rhomboid-like-2 (RHBDL2), an evolutionally conserved intramembrane serine protease, can cleave the EGF ligand and thus trigger EGFR activation. Herein, we demonstrated that RHBDL2 overexpression in human epithelial cells resulted in promotion of cell proliferation, reduction of cell adhesion, and suppression of anoikis. During long-term suspension cultures, increased RHBDL2 was only detected in aggressive tumor cell lines. Treatment with the rhomboid protease inhibitor or RHBDL2 shRNA increased cleaved caspase 3, a marker of apoptosis. Finally, inhibition of EGFR activation increased the cleaved caspase 3 and attenuated the detachment-induced focal adhesion kinase phosphorylation. Taken together, these findings provide evidence for the first time that RHBDL2 is a critical molecule in anoikis resistance of malignant epithelial cells, possibly through the EGFR-mediated signaling. Our study demonstrates RHBDL2 as a new therapeutic target for cancer metastasis.

scholarly journals The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1909
Author(s):  
Tatiana S. Gerashchenko ◽  
Sofia Y. Zolotaryova ◽  
Artem M. Kiselev ◽  
Liubov A. Tashireva ◽  
Nikita M. Novikov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Ether Lipid ◽  
Metastatic Tumor ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Invasive Component ◽  
Positive Expression

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

scholarly journals Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1539 ◽  
Author(s):  
Peter Ping Lin
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Mesenchymal Transition ◽  
Tumor Neovascularization ◽  
Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4583-4591 ◽  
Author(s):  
Heinz Läubli ◽  
Katharina-Susanne Spanaus ◽  
Lubor Borsig
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Metastatic Tumor ◽  
Microvascular Endothelial Cells ◽  
Hematogenous Metastasis ◽  
Specific Gene ◽  
Microvascular Endothelium ◽  
Endothelial Response ◽  
Microvascular Endothelial ◽  
Metastatic Microenvironment

Abstract Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment.

scholarly journals When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition

2016 ◽  
Vol 310 (9) ◽  
pp. H1055-H1063 ◽  
Author(s):  
Ákos Gasparics ◽  
László Rosivall ◽  
István A. Krizbai ◽  
Attila Sebe
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Metastatic Tumor ◽  
Therapeutic Approaches ◽  
Mesenchymal Transition ◽  
New Therapeutic Approaches ◽  
Pathological Conditions ◽  
Junctional Protein ◽  
Endothelial Mesenchymal Transition ◽  
Organ Fibrosis

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.

scholarly journals Metastatic Tumor Cells Exploit Their Adhesion Repertoire to Counteract Shear Forces During Intravascular Arrest

2019 ◽  
Author(s):  
Nael Osmani ◽  
Gautier Follain ◽  
Maria Jesus Garcia-Leon ◽  
Olivier Lefebvre ◽  
Ignacio Busnelli ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Metastatic Tumor ◽  
Shear Forces

Abstract 3380: Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells

2016 ◽  
Author(s):  
Monica Burgett ◽  
Justin Lathia ◽  
Patrick Roth ◽  
Amy Nowacki ◽  
Elena Pugacheva ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Direct Contact ◽  
Integrin Αvβ3 ◽  
And Migration

scholarly journals Obesity and Cancer Metastasis: Molecular and Translational Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3798
Author(s):  
Stephanie Annett ◽  
Gillian Moore ◽  
Tracy Robson
Keyword(s):  
Adipose Tissue ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Metastatic Tumor ◽  
Established Risk Factor ◽  
Metastatic Behavior ◽  
Obesity And Cancer ◽  
Enhance Tumor Growth

Obesity is a modern health problem that has reached pandemic proportions. It is an established risk factor for carcinogenesis, however, evidence for the contribution of adipose tissue to the metastatic behavior of tumors is also mounting. Over 90% of cancer mortality is attributed to metastasis and metastatic tumor cells must communicate with their microenvironment for survival. Many of the characteristics observed in obese adipose tissue strongly mirror the tumor microenvironment. Thus in the case of prostate, pancreatic and breast cancer and esophageal adenocarcinoma, which are all located in close anatomical proximity to an adipose tissue depot, the adjacent fat provides an ideal microenvironment to enhance tumor growth, progression and metastasis. Adipocytes provide adipokines, fatty acids and other soluble factors to tumor cells whilst immune cells infiltrate the tumor microenvironment. In addition, there are emerging studies on the role of the extracellular vesicles secreted from adipose tissue, and the extracellular matrix itself, as drivers of obesity-induced metastasis. In the present review, we discuss the major mechanisms responsible for the obesity–metastatic link. Furthermore, understanding these complex mechanisms will provide novel therapies to halt the tumor–adipose tissue crosstalk with the ultimate aim of inhibiting tumor progression and metastatic growth.

scholarly journals Breast Cancer Metastasis in the Skin with Hyperkeratotic Pigmentation Caused by Melanocyte Colonization

2018 ◽  
Vol 11 (3) ◽  
pp. 660-664
Author(s):  
Shino Ishihara-Yusa ◽  
Taku Fujimura ◽  
Chunbing Lyu ◽  
Masayuki Sugawara ◽  
Kazuhiro Sakamoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immunohistochemical Staining ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Rare Condition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Keratinocyte Proliferation

Pigmented breast cancer in the skin caused by nonneoplastic melanocytes of epidermal origin is a rare condition of metastasis from breast cancer, but the pathogenesis of this phenomenon is almost unknown. In this report, we describe a case of breast cancer metastasis in the skin with prominent hyperkeratotic pigmentation caused by nonneoplastic melanocyte colonization. Immunohistochemical staining revealed that the metastatic tumor cells produced IL-23, which is reported not only to induce IL-17 but also to inhibit cell apoptosis in breast cancer cells, which affects tumor progression. In addition to IL-23, substantial numbers of IL-17-producing cells were detected at the peritumoral area, suggesting that IL-17 might induce not only melanogenesis but also keratinocyte proliferation and tumorigenesis. Our report suggests possible mechanisms of hyperkeratotic pigmentation of breast cancer metastasis in the skin.

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