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18 pages, 3756 KiB

Open AccessArticle

Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

by Chi-Chung Wang, Yuan-Ling Hsu, Chi-Jen Chang, Chia-Jen Wang, Tzu-Hung Hsiao and Szu-Hua Pan

Cancers 2019, 11(12), 2021; https://doi.org/10.3390/cancers11122021 - 14 Dec 2019

Cited by 11 | Viewed by 3786

Abstract

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research [...] Read more.

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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22 pages, 3058 KiB

Open AccessArticle

Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines

by Nour Jalaleddine, Layal El-Hajjar, Hassan Dakik, Abdullah Shaito, Jessica Saliba, Rémi Safi, Kazem Zibara and Marwan El-Sabban

Cancers 2019, 11(12), 1967; https://doi.org/10.3390/cancers11121967 - 7 Dec 2019

Cited by 30 | Viewed by 6154

Abstract

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution [...] Read more.

Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers. In addition, PANX1 inhibition or genetic ablation decreased the invasiveness of MDA-MB-231 cells. Our results suggest PANX1 overexpression in breast cancer is associated with a shift towards an EMT phenotype, in silico and in vitro, attributing to it a tumor-promoting effect, with poorer clinical outcomes in breast cancer patients. This association offers a novel target for breast cancer therapy. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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16 pages, 2098 KiB

Open AccessArticle

Size and Shape Filtering of Malignant Cell Clusters within Breast Tumors Identifies Scattered Individual Epithelial Cells as the Most Valuable Histomorphological Clue in the Prognosis of Distant Metastasis Risk

by Velicko Vranes, Nemanja Rajković, Xingyu Li, Konstantinos N. Plataniotis, Nataša Todorović Raković, Jelena Milovanović, Ksenija Kanjer, Marko Radulovic and Nebojša T. Milošević

Cancers 2019, 11(10), 1615; https://doi.org/10.3390/cancers11101615 - 22 Oct 2019

Cited by 12 | Viewed by 3158

Abstract

Survival and life quality of breast cancer patients could be improved by more aggressive chemotherapy for those at high metastasis risk and less intense treatments for low-risk patients. Such personalized treatment cannot be currently achieved due to the insufficient reliability of metastasis risk [...] Read more.

Survival and life quality of breast cancer patients could be improved by more aggressive chemotherapy for those at high metastasis risk and less intense treatments for low-risk patients. Such personalized treatment cannot be currently achieved due to the insufficient reliability of metastasis risk prognosis. The purpose of this study was therefore, to identify novel histopathological prognostic markers of metastasis risk through exhaustive computational image analysis of 80 size and shape subsets of epithelial clusters in breast tumors. The group of 102 patients had a follow-up median of 12.3 years, without lymph node spread and systemic treatments. Epithelial cells were stained by the AE1/AE3 pan-cytokeratin antibody cocktail. The size and shape subsets of the stained epithelial cell clusters were defined in each image by use of the circularity and size filters and analyzed for prognostic performance. Epithelial areas with the optimal prognostic performance were uniformly small and round and could be recognized as individual epithelial cells scattered in tumor stroma. Their count achieved an area under the receiver operating characteristic curve (AUC) of 0.82, total area (AUC = 0.77), average size (AUC = 0.63), and circularity (AUC = 0.62). In conclusion, by use of computational image analysis as a hypothesis-free discovery tool, this study reveals the histomorphological marker with a high prognostic value that is simple and therefore easy to quantify by visual microscopy. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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17 pages, 5207 KiB

Open AccessArticle

CD200 Induces Epithelial-to-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma via β-Catenin-Mediated Nuclear Translocation

by Seung-Phil Shin, Ah Ra Goh, Hyeon-Gu Kang, Seok-Jun Kim, Jong-Kwang Kim, Kyung-Tae Kim, John H Lee, Yong-Soo Bae, Yuh-Seog Jung and Sang-Jin Lee

Cancers 2019, 11(10), 1583; https://doi.org/10.3390/cancers11101583 - 17 Oct 2019

Cited by 11 | Viewed by 3697

Abstract

The membrane glycoprotein CD200 binds to its receptor CD200R1 and induces tolerance, mainly in cells of the myeloid lineage; however, information regarding its role in solid tumors is limited. Here, we investigated whether CD200 expression, which is enriched mainly in high-grade head and [...] Read more.

The membrane glycoprotein CD200 binds to its receptor CD200R1 and induces tolerance, mainly in cells of the myeloid lineage; however, information regarding its role in solid tumors is limited. Here, we investigated whether CD200 expression, which is enriched mainly in high-grade head and neck squamous cell carcinoma (HNSCC), correlates with cancer progression, particularly the epithelial-to-mesenchymal transition (EMT). The forced overexpression of CD200 in the HNSCC cell line, UMSCC84, not only increased the expression of EMT-related genes, but also enhanced invasiveness. The cleaved cytoplasmic domain of CD200 interacted with β-catenin in the cytosol, was translocated to the nucleus, and eventually enhanced EMT-related gene expression. CD200 increased the invasiveness of mouse tonsillar epithelium immortalized with E6, E7, and Ras (MEER), a model of tonsillar squamous cell carcinoma. siRNA inhibition of CD200 or extracellular domain of CD200R1 down-regulated the expression of EMT-related genes and decreased invasiveness. Consistently, compared to CD200-null MEER tumors, subcutaneous CD200-expressing MEER tumors showed significantly increased metastatic migration into draining lymph nodes. Our study demonstrates a novel and unique role of CD200 in inducing EMT, suggesting the potential therapeutic target for blocking solid cancer progression. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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12 pages, 3198 KiB

Open AccessArticle

Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases

by Paula S. Ginter, George S. Karagiannis, David Entenberg, Yu Lin, John Condeelis, Joan G. Jones and Maja H. Oktay

Cancers 2019, 11(10), 1507; https://doi.org/10.3390/cancers11101507 - 8 Oct 2019

Cited by 28 | Viewed by 5689

Abstract

Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, [...] Read more.

Cancer cells metastasize from primary tumors to regional lymph nodes and distant sites via the lymphatic and blood vascular systems, respectively. Our prior work has demonstrated that in primary breast tumors, cancer cells utilize a three-cell complex (known as tumor microenvironment of metastasis, or TMEM) composed of a perivascular macrophage, a tumor cell expressing high levels of the actin-regulatory protein mammalian enabled (Mena), and an endothelial cell as functional “doorways” for hematogenous dissemination. Here, we studied a well-annotated case–control cohort of human invasive ductal carcinoma of the breast and metastatic lymph nodes from a separate breast cancer cohort. We demonstrate that in primary breast tumors, blood vessels are always present within tumor cell nests (TCNs) and tumor-associated stroma (TAS), while lymphatic vessels are only occasionally present in TCN and TAS. Furthermore, TMEM doorways not only exist in primary tumors as previously reported but also in lymph node metastases. In addition, we show that TMEM intravasation doorways are restricted to the blood vascular endothelium in both primary tumors and lymph node metastases, suggesting that breast cancer dissemination to distant sites from both primary tumors and metastatic foci in lymph nodes occurs hematogenously at TMEM doorways. TMEMs are very rarely detected at lymphatic vessels and do not confer clinical prognostic significance, indicating they are not participants in TMEM-associated hematogenous dissemination. These findings are consistent with recent observations that hematogenous dissemination from lymph nodes occurs via blood vessels. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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23 pages, 6592 KiB

Open AccessArticle

CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis

by Cynthia M. Simbulan-Rosenthal, Ryan Dougherty, Sahar Vakili, Alexandra M. Ferraro, Li-Wei Kuo, Ryyan Alobaidi, Leala Aljehane, Anirudh Gaur, Peter Sykora, Eric Glasgow, Seema Agarwal and Dean S. Rosenthal

Cancers 2019, 11(10), 1490; https://doi.org/10.3390/cancers11101490 - 3 Oct 2019

Cited by 25 | Viewed by 6150

Abstract

CD133, known as prominin1, is a penta-span transmembrane glycoprotein presumably a cancer stem cell marker for carcinomas, glioblastomas, and melanomas. We showed that CD133(+) ‘melanoma-initiating cells’ are associated with chemoresistance, contributing to poor patient outcome. The current study investigates the role(s) of CD133 [...] Read more.

CD133, known as prominin1, is a penta-span transmembrane glycoprotein presumably a cancer stem cell marker for carcinomas, glioblastomas, and melanomas. We showed that CD133(+) ‘melanoma-initiating cells’ are associated with chemoresistance, contributing to poor patient outcome. The current study investigates the role(s) of CD133 in invasion and metastasis. Magnetic-activated cell sorting of a melanoma cell line (BAKP) followed by transwell invasion assays revealed that CD133(+) cells are significantly more invasive than CD133(−) cells. Conditional reprogramming of BAKP CD133(+) cells maintained stable CD133 overexpression (BAK-R), and induced cancer stem cell markers, melanosphere formation, and chemoresistance to kinase inhibitors. BAK-R cells showed upregulated CD133 expression, and consequently were more invasive and metastatic than BAK-P cells in transwell and zebrafish assays. CD133 knockdown by siRNA or CRISPR-Cas9 (BAK-R-T3) in BAK-R cells reduced invasion and levels of matrix metalloproteinases MMP2/MMP9. BAK-R-SC cells, but not BAK-R-T3, were metastatic in zebrafish. While CD133 knockdown by siRNA or CRISPR-Cas9 in BAK-P cells attenuated invasion and diminished MMP2/MMP9 levels, doxycycline-induced CD133 expression in BAK-P cells enhanced invasion and MMP2/MMP9 concentrations. CD133 may therefore play an essential role in invasion and metastasis via upregulation of MMP2/MMP9, leading to tumor progression, and represents an attractive target for intervention in melanoma. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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18 pages, 4376 KiB

Open AccessArticle

Arl13b Regulates Breast Cancer Cell Migration and Invasion by Controlling Integrin-Mediated Signaling

by Cristina Casalou, Alexandra Faustino, Fernanda Silva, Inês C. Ferreira, Daniela Vaqueirinho, Andreia Ferreira, Pedro Castanheira, Teresa Barona, José S. Ramalho, Jacinta Serpa, Ana Félix and Duarte C. Barral

Cancers 2019, 11(10), 1461; https://doi.org/10.3390/cancers11101461 - 29 Sep 2019

Cited by 9 | Viewed by 5030

Abstract

Breast cancer is the first cause of cancer-related mortality among women worldwide, according to the most recent estimates. This mortality is mainly caused by the tumors’ ability to form metastases. Cancer cell migration and invasion are essential for metastasis and rely on the [...] Read more.

Breast cancer is the first cause of cancer-related mortality among women worldwide, according to the most recent estimates. This mortality is mainly caused by the tumors’ ability to form metastases. Cancer cell migration and invasion are essential for metastasis and rely on the interplay between actin cytoskeleton remodeling and cell adhesion. Therefore, understanding the mechanisms by which cancer cell invasion is controlled may provide new strategies to impair cancer progression. We investigated the role of the ADP-ribosylation factor (Arf)-like (Arl) protein Arl13b in breast cancer cell migration and invasion in vitro, using breast cancer cell lines and in vivo, using mouse orthotopic models. We show that Arl13b silencing inhibits breast cancer cell migration and invasion in vitro, as well as cancer progression in vivo. We also observed that Arl13b is upregulated in breast cancer cell lines and patient tissue samples. Moreover, we found that Arl13b localizes to focal adhesions (FAs) and interacts with β3-integrin. Upon Arl13b silencing, β3-integrin cell surface levels and FA size are increased and integrin-mediated signaling is inhibited. Therefore, we uncover a role for Arl13b in breast cancer cell migration and invasion and provide a new mechanism for how ARL13B can function as an oncogene, through the modulation of integrin-mediated signaling. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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16 pages, 2460 KiB

Open AccessArticle

P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis

by Jan-Hendrik Venhuizen, Paul N. Span, Koen van den Dries, Sebastian Sommer, Peter Friedl and Mirjam M. Zegers

Cancers 2019, 11(10), 1459; https://doi.org/10.3390/cancers11101459 - 29 Sep 2019

Cited by 11 | Viewed by 4044

Abstract

Tumor metastasis is the endpoint of tumor progression and depends on the ability of tumor cells to locally invade tissue, transit through the bloodstream and ultimately to colonize secondary organs at distant sites. P120 catenin (p120) has been implicated as an important regulator [...] Read more.

Tumor metastasis is the endpoint of tumor progression and depends on the ability of tumor cells to locally invade tissue, transit through the bloodstream and ultimately to colonize secondary organs at distant sites. P120 catenin (p120) has been implicated as an important regulator of metastatic dissemination because of its roles in cell–cell junctional stability, cytoskeletal dynamics, growth and survival. However, conflicting roles for p120 in different tumor models and steps of metastasis have been reported, and the understanding of p120 functions is confounded by the differential expression of p120 isoforms, which differ in N-terminal length, tissue localization and, likely, function. Here, we used in silico exon expression analyses, in vitro invasion assays and both RT-PCR and immunofluorescence of human tumors. We show that alternative exon usage favors expression of short isoform p120-3 in 1098 breast tumors and correlates with poor prognosis. P120-3 is upregulated at the invasive front of breast cancer cells migrating as collective groups in vitro. Furthermore, we demonstrate in histological sections of 54 human breast cancer patients that p120-3 expression is maintained throughout the metastatic cascade, whereas p120-1 is differentially expressed and diminished during invasion and in metastases. These data suggest specific regulation and functions of p120-3 in breast cancer invasion and metastasis. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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15 pages, 3050 KiB

Open AccessArticle

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells

by Samuel Martínez-Meza, Jorge Díaz, Alejandra Sandoval-Bórquez, Manuel Valenzuela-Valderrama, Natalia Díaz-Valdivia, Victoria Rojas-Celis, Pamela Contreras, Ricardo Huilcaman, María Paz Ocaranza, Mario Chiong, Lisette Leyton, Sergio Lavandero and Andrew F.G. Quest

Cancers 2019, 11(9), 1299; https://doi.org/10.3390/cancers11091299 - 3 Sep 2019

Cited by 18 | Viewed by 3989

Abstract

The renin–angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 [...] Read more.

The renin–angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the anti-metastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDA-MB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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17 pages, 2226 KiB

Open AccessArticle

Coordinated Expression of Ras Suppressor 1 (RSU-1) and Growth Differentiation Factor 15 (GDF15) Affects Glioma Cell Invasion

by Maria Louca, Vasiliki Gkretsi and Triantafyllos Stylianopoulos

Cancers 2019, 11(8), 1159; https://doi.org/10.3390/cancers11081159 - 13 Aug 2019

Cited by 9 | Viewed by 4378

Abstract

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor due to its invasive phenotype. Ras suppressor 1 (RSU-1) is a cell-extracellular matrix adhesion protein and we recently found that it promotes cell invasion in aggressive cells and inhibits it in non-invasive. [...] Read more.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor due to its invasive phenotype. Ras suppressor 1 (RSU-1) is a cell-extracellular matrix adhesion protein and we recently found that it promotes cell invasion in aggressive cells and inhibits it in non-invasive. Growth differentiation factor-15 (GDF15) is known to be involved in actin cytoskeleton reorganization and metastasis. In this study, we used three brain cell lines (H4, SW1088 and A172) with increasing RSU-1 expression levels and invasive capacity and decreasing GDF15 levels to investigate the interplay between RSU-1 and GDF15 with regard to cell invasion. Four experimental approaches were used: (a) GDF15 treatment, (b) Rsu-1 silencing, (c) GDF15 silencing, and (d) combined GDF15 treatment and RSU-1 silencing. We found that the differential expression of RSU-1 and GDF15 in H4 and A172 cells leading to inhibition of cell invasion in H4 cells and promotion in A172 through respective changes in PINCH1, RhoA and MMP-13 expression. Interestingly SW1088, with intermediate RSU-1 and GDF15 expression, were not affected by any treatment. We conclude that there is a strong connection between RSU-1 and GDF15 in H4, SW1088 and A172 cells and the relative expression of these two proteins is fundamental in affecting their invasive fate. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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21 pages, 5668 KiB

Open AccessArticle

Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation

by Maximiliano Arce, Mauricio P. Pinto, Macarena Galleguillos, Catalina Muñoz, Soledad Lange, Carolina Ramirez, Rafaela Erices, Pamela Gonzalez, Ethel Velasquez, Fabián Tempio, Mercedes N. Lopez, Flavio Salazar-Onfray, Kelly Cautivo, Alexis M. Kalergis, Sebastián Cruz, Álvaro Lladser, Lorena Lobos-González, Guillermo Valenzuela, Nixa Olivares, Claudia Sáez, Tania Koning, Fabiola A. Sánchez, Patricia Fuenzalida, Alejandro Godoy, Pamela Contreras Orellana, Lisette Leyton, Roberta Lugano, Anna Dimberg, Andrew F.G. Quest and Gareth I. Owen Show full author list Hide full author list

Cancers 2019, 11(8), 1103; https://doi.org/10.3390/cancers11081103 - 2 Aug 2019

Cited by 18 | Viewed by 4974

Abstract

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors [...] Read more.

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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18 pages, 8205 KiB

Open AccessArticle

Harnessing Induced Essentiality: Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts

by Eva-Maria E. Hedlund, Paul C. McDonald, Oksana Nemirovsky, Shannon Awrey, Lasse D.E. Jensen and Shoukat Dedhar

Cancers 2019, 11(7), 1002; https://doi.org/10.3390/cancers11071002 - 17 Jul 2019

Cited by 37 | Viewed by 4371

Abstract

Triple Negative Breast Cancer (TNBC) is aggressive, metastatic and drug-resistant, limiting the spectrum of effective therapeutic options for breast cancer patients. To date, anti-angiogenic agents have had limited success in the treatment of systemic breast cancer, possibly due to the exacerbation of tumor [...] Read more.

Triple Negative Breast Cancer (TNBC) is aggressive, metastatic and drug-resistant, limiting the spectrum of effective therapeutic options for breast cancer patients. To date, anti-angiogenic agents have had limited success in the treatment of systemic breast cancer, possibly due to the exacerbation of tumor hypoxia and increased metastasis. Hypoxia drives increased expression of downstream effectors, including Carbonic Anhydrase IX (CAIX), a critical functional component of the pro-survival machinery required by hypoxic tumor cells. Here, we used the highly metastatic, CAIX-positive MDA-MB-231 LM2-4 orthotopic model of TNBC to investigate whether combinatorial targeting of CAIX and angiogenesis impacts tumor growth and metastasis in vivo to improve efficacy. The administration of a small molecule inhibitor of CAIX, SLC-0111, significantly reduced overall metastatic burden, whereas exposure to sunitinib increased hypoxia and CAIX expression in primary tumors, and failed to inhibit metastasis. The administration of SLC-0111 significantly decreased primary tumor vascular density and permeability, and reduced metastasis to the lung and liver. Furthermore, combining sunitinib and SLC-0111 significantly reduced both primary tumor growth and sunitinib-induced metastasis to the lung. Our findings suggest that targeting angiogenesis and hypoxia effectors in combination holds promise as a novel rational strategy for the effective treatment of patients with TNBC. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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13 pages, 2465 KiB

Open AccessArticle

Increased Soluble CrkL in Serum of Breast Cancer Patients Is Associated with Advanced Disease

by Srimeenakshi Srinivasan and Biana Godin

Cancers 2019, 11(7), 961; https://doi.org/10.3390/cancers11070961 - 9 Jul 2019

Cited by 5 | Viewed by 3274

Abstract

Over-expression of Crk-like protein (CrkL), an intracellular adaptor protein, in breast cancer biopsies has been linked to poor prognosis. CrkL can be secreted from cancer cells binding to β1 integrin on the cell membrane. In this study, we evaluated, for the first time, [...] Read more.

Over-expression of Crk-like protein (CrkL), an intracellular adaptor protein, in breast cancer biopsies has been linked to poor prognosis. CrkL can be secreted from cancer cells binding to β1 integrin on the cell membrane. In this study, we evaluated, for the first time, the levels of soluble CrkL in serum of breast cancer patients. Expression of CrkL and secreted fractions from human breast cancer cell lines and clinical patient samples were assessed by immunohistochemistry and Enzyme Linked Immuno-Sorbent Assay (ELISA). CrkL levels in tissues and sera of patients with different disease stages were compared and statistically analyzed by Chi-square test and Student’s t-test. Culture media from human breast cancer cell lines SUM159, MDA-MB231, and MCF7 showed over a 21-, 15-, and 11-fold higher concentration of soluble CrkL as compared to normal breast epithelium cell line MCF10A. Expression of CrkL was elevated in 85% of breast tumor tissue sections. Serum levels of CrkL were significantly higher in breast cancer patients than in healthy donors. All patients with metastatic disease had significantly elevated concentration of soluble CrkL in the serum with on average three-fold increase from the baseline. The data suggest that soluble fraction of CrkL can be further evaluated as a serum biomarker for advanced disease in breast cancer patients. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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22 pages, 7890 KiB

Open AccessArticle

Mechanisms behind Temsirolimus Resistance Causing Reactivated Growth and Invasive Behavior of Bladder Cancer Cells In Vitro

by Eva Juengel, Iyad Natsheh, Ramin Najafi, Jochen Rutz, Igor Tsaur, Axel Haferkamp, Felix K.-H. Chun and Roman A. Blaheta

Cancers 2019, 11(6), 777; https://doi.org/10.3390/cancers11060777 - 4 Jun 2019

Cited by 8 | Viewed by 3385

Abstract

Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared [...] Read more.

Background: Although mechanistic target of rapamycin (mTOR) inhibitors, such as temsirolimus, show promise in treating bladder cancer, acquired resistance often hampers efficacy. This study evaluates mechanisms leading to resistance. Methods: Cell growth, proliferation, cell cycle phases, and cell cycle regulating proteins were compared in temsirolimus resistant (res) and sensitive (parental—par) RT112 and UMUC3 bladder cancer cells. To evaluate invasive behavior, adhesion to vascular endothelium or to immobilized extracellular matrix proteins and chemotactic activity were examined. Integrin α and β subtypes were analyzed and blocking was done to evaluate physiologic integrin relevance. Results: Growth of RT112res could no longer be restrained by temsirolimus and was even enhanced in UMUC3res, accompanied by accumulation in the S- and G2/M-phase. Proteins of the cdk-cyclin and Akt-mTOR axis increased, whereas p19, p27, p53, and p73 decreased in resistant cells treated with low-dosed temsirolimus. Chemotactic activity of RT112res/UMUC3res was elevated following temsirolimus re-exposure, along with significant integrin α2, α3, and β1 alterations. Blocking revealed a functional switch of the integrins, driving the resistant cells from being adhesive to being highly motile. Conclusion: Temsirolimus resistance is associated with reactivation of bladder cancer growth and invasive behavior. The α2, α3, and β1 integrins could be attractive treatment targets to hinder temsirolimus resistance. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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14 pages, 7223 KiB

Open AccessArticle

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

by Martyna Pakuła, Paweł Uruski, Arkadiusz Niklas, Aldona Woźniak, Dariusz Szpurek, Andrzej Tykarski, Justyna Mikuła-Pietrasik and Krzysztof Książek

Cancers 2019, 11(5), 662; https://doi.org/10.3390/cancers11050662 - 13 May 2019

Cited by 11 | Viewed by 3306

Abstract

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal [...] Read more.

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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15 pages, 5568 KiB

Open AccessArticle

Cul4A Modulates Invasion and Metastasis of Lung Cancer through Regulation of ANXA10

by Ming-Szu Hung, Yi-Chuan Chen, Paul-Yann Lin, Ya-Chin Li, Chia-Chen Hsu, Jr-Hau Lung, Liang You, Zhidong Xu, Jian-Hua Mao, David M. Jablons and Cheng-Ta Yang

Cancers 2019, 11(5), 618; https://doi.org/10.3390/cancers11050618 - 2 May 2019

Cited by 19 | Viewed by 3940

Abstract

Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer [...] Read more.

Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer (NSCLC) tissues and the overexpression of Cul4A was associated with poor prognosis after surgical resection and it also decreased the expression of the tumor suppressor protein annexin A10 (ANXA10). The knockdown of Cul4A was associated with the upregulation of ANXA10, and the forced expression of Cul4A was associated with the downregulation of ANXA10 in lung cancer cells. Further studies showed that the knockdown of Cul4A inhibited the invasion and metastasis of lung cancer cells, which was reversed by the further knockdown of ANXA10. In addition, the knockdown of Cul4A inhibited lung tumor metastasis in mouse tail vein injection xenograft models. Notably, Cul4A regulated the degradation of ANXA10 through its interaction with ANXA10 and ubiquitination in lung cancer cells. Our findings suggest that Cul4A is a prognostic marker in NSCLC patients, and Cul4A plays important roles in lung cancer invasion and metastasis through the regulation of the ANXA10 tumor suppressor. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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15 pages, 14564 KiB

Open AccessArticle

Targeting the mDia Formin-Assembled Cytoskeleton Is an Effective Anti-Invasion Strategy in Adult High-Grade Glioma Patient-Derived Neurospheres

by Krista M. Pettee, Kathryn N. Becker, Arthur S. Alberts, Kevin A. Reinard, Jason L. Schroeder and Kathryn M. Eisenmann

Cancers 2019, 11(3), 392; https://doi.org/10.3390/cancers11030392 - 20 Mar 2019

Cited by 13 | Viewed by 3983

Abstract

High-grade glioma (HGG, WHO Grade III–IV) accounts for the majority of adult primary malignant brain tumors. Failure of current therapies to target invasive glioma cells partly explains the minimal survival advantages: invasive tumors lack easily-defined surgical margins, and are inherently more chemo- and [...] Read more.

High-grade glioma (HGG, WHO Grade III–IV) accounts for the majority of adult primary malignant brain tumors. Failure of current therapies to target invasive glioma cells partly explains the minimal survival advantages: invasive tumors lack easily-defined surgical margins, and are inherently more chemo- and radioresistant. Much work centers upon Rho GTPase-mediated glioma invasion, yet downstream Rho effector roles are poorly understood and represent potential therapeutic targets. The roles for the mammalian Diaphanous (mDia)-related formin family of Rho effectors have emerged in invasive/metastatic disease. mDias assemble linear F-actin to promote protrusive cytoskeletal structures underlying tumor cell invasion. Small molecule mDia intramimic (IMM) agonists induced mDia functional activities including F-actin polymerization. mDia agonism inhibited polarized migration in Glioblastoma (WHO Grade IV) cells in three-dimensional (3D) in vitro and rat brain slice models. Here, we evaluate whether clinically-relevant high-grade glioma patient-derived neuro-sphere invasion is sensitive to formin agonism. Surgical HGG samples were dissociated, briefly grown as monolayers, and spontaneously formed non-adherent neuro-spheres. IMM treatment dramatically inhibited HGG patient neuro-sphere invasion, both at neuro-sphere embedding and mid-invasion assay, inducing an amoeboid morphology in neuro-sphere edge cells, while inhibiting actin- and tubulin-enriched tumor microtube formation. Thus, mDia agonism effectively disrupts multiple aspects of patient-derived HGG neuro-sphere invasion. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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20 pages, 1412 KiB

Open AccessFeature PaperReview

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

by Mustafa B. A. Djamgoz, Scott P. Fraser and William J. Brackenbury

Cancers 2019, 11(11), 1675; https://doi.org/10.3390/cancers11111675 - 28 Oct 2019

Cited by 87 | Viewed by 6367

Abstract

A wide body of evidence suggests that voltage-gated sodium channels (VGSCs) are expressed de novo in several human carcinomas where channel activity promotes a variety of cellular behaviours integral to the metastatic cascade. These include directional motility (including galvanotaxis), pH balance, extracellular proteolysis, [...] Read more.

A wide body of evidence suggests that voltage-gated sodium channels (VGSCs) are expressed de novo in several human carcinomas where channel activity promotes a variety of cellular behaviours integral to the metastatic cascade. These include directional motility (including galvanotaxis), pH balance, extracellular proteolysis, and invasion. Contrary to the substantial in vitro data, however, evidence for VGSC involvement in the cancer process in vivo is limited. Here, we critically assess, for the first time, the available in vivo evidence, hierarchically from mRNA level to emerging clinical aspects, including protein-level studies, electrolyte content, animal tests, and clinical imaging. The evidence strongly suggests that different VGSC subtypes (mainly Nav1.5 and Nav1.7) are expressed de novo in human carcinoma tissues and generally parallel the situation in vitro. Consistent with this, tissue electrolyte (sodium) levels, quantified by clinical imaging, are significantly higher in cancer vs. matched non-cancer tissues. These are early events in the acquisition of metastatic potential by the cancer cells. Taken together, the multi-faceted evidence suggests that the VGSC expression has clinical (diagnostic and therapeutic) potential as a prognostic marker, as well as an anti-metastatic target. The distinct advantages offered by the VGSC include especially (1) its embryonic nature, demonstrated most clearly for the predominant neonatal Nav1.5 expression in breast and colon cancer, and (2) the specifically druggable persistent current that VGSCs develop under hypoxic conditions, as in growing tumours, which promotes invasiveness and metastasis. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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21 pages, 1713 KiB

Open AccessReview

The Pivotal Roles of the Epithelial Membrane Protein Family in Cancer Invasiveness and Metastasis

by Mohammad Khusni B. Ahmat Amin, Akio Shimizu and Hisakazu Ogita

Cancers 2019, 11(11), 1620; https://doi.org/10.3390/cancers11111620 - 23 Oct 2019

Cited by 34 | Viewed by 6649

Abstract

The members of the family of epithelial membrane proteins (EMPs), EMP1, EMP2, and EMP3, possess four putative transmembrane domain structures and are composed of approximately 160 amino acid residues. EMPs are encoded by the growth arrest-specific 3 (GAS3)/peripheral myelin protein 22 kDa (PMP22) [...] Read more.

The members of the family of epithelial membrane proteins (EMPs), EMP1, EMP2, and EMP3, possess four putative transmembrane domain structures and are composed of approximately 160 amino acid residues. EMPs are encoded by the growth arrest-specific 3 (GAS3)/peripheral myelin protein 22 kDa (PMP22) gene family. The GAS3/PMP22 family members play roles in cell migration, growth, and differentiation. Evidence indicates an association of these molecules with cancer progression and metastasis. Each EMP has pro- and anti-metastatic functions that are likely involved in the complex mechanisms of cancer progression. We have recently demonstrated that the upregulation of EMP1 expression facilitates cancer cell migration and invasion through the activation of a small GTPase, Rac1. The inoculation of prostate cancer cells overexpressing EMP1 into nude mice leads to metastasis to the lymph nodes and lungs, indicating that EMP1 contributes to metastasis. Pro-metastatic properties of EMP2 and EMP3 have also been proposed. Thus, targeting EMPs may provide new insights into their clinical utility. Here, we highlight the important aspects of EMPs in cancer biology, particularly invasiveness and metastasis, and describe recent therapeutic approaches. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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24 pages, 449 KiB

Open AccessReview

Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism?

by Franz Sellner

Cancers 2019, 11(9), 1379; https://doi.org/10.3390/cancers11091379 - 17 Sep 2019

Cited by 10 | Viewed by 2865

Abstract

Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic–haematogenic metastasis route [...] Read more.

Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic–haematogenic metastasis route (uniform distribution of the metastases across the pancreas and independence of the metastatic localization in the pancreas of the side of the renal carcinoma); and (b) postulate a high impact of a seed and soil mechanism (SSM) on isolated pancreatic metastasis of renal cell carcinoma (isPM) as an explanation for exclusive pancreatic metastases, despite a systemic haematogenous tumor cell embolization. The objective of the study presented was to search for further arguments in favor of an SSM with isPM. For that purpose, the factor’s histology, grading, and singular/multiple pancreas metastases were analyzed on the basis of 814 observations published up to 2018. While histology and grading allowed for no conclusions regarding the importance of an SSM, the comparison of singular/multiple pancreas metastases produced arguments in favor of an SSM: 1. The multiple pancreas metastases observed in 38.1% prove that multiple tumor cell embolisms occur with isPM, the exclusive “maturation” of which in the pancreas requires an SSM; 2. The survival rates (SVR), which are consistent with singular and multiple pancreas metastases (despite the higher total tumor load with the latter), prove that the metastasized tumor cells are not able to survive in all other organs because of an SSM, which results in identical SVR when the pancreatic foci are treated adequately. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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15 pages, 271 KiB

Open AccessReview

Local Treatment of Breast Cancer Liver Metastasis

by Reto Bale, Daniel Putzer and Peter Schullian

Cancers 2019, 11(9), 1341; https://doi.org/10.3390/cancers11091341 - 11 Sep 2019

Cited by 88 | Viewed by 7532

Abstract

Breast cancer represents a leading cause of death worldwide. Despite the advances in systemic therapies, the prognosis for patients with breast cancer liver metastasis (BCLM) remains poor. Especially in case of failure or cessation of systemic treatments, surgical resection for BCLMs has been [...] Read more.

Breast cancer represents a leading cause of death worldwide. Despite the advances in systemic therapies, the prognosis for patients with breast cancer liver metastasis (BCLM) remains poor. Especially in case of failure or cessation of systemic treatments, surgical resection for BCLMs has been considered as the treatment standard despite a lack of robust evidence of benefit. However, due to the extent and location of disease and physical condition, the number of patients with BCLM who are eligible for surgery is limited. Palliative locoregional treatments of liver metastases (LM) include transarterial embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiotherapy (SIRT). Percutaneous thermal ablation methods, such as radiofrequency ablation (RFA) and microwave ablation (MWA), are considered potentially curative local treatment options. They are less invasive, less expensive and have fewer contraindications and complication rates than surgery. Because conventional ultrasound- and computed tomography-guided single-probe thermal ablation is limited by tumor size, multi-probe stereotactic radiofrequency ablation (SRFA) with intraoperative image fusion for immediate, reliable judgment has been developed in order to treat large and multiple tumors within one session. This review focuses on the different minimally invasive local and locoregional treatment options for BCLM and attempts to describe their current and future role in the multidisciplinary treatment setting. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

27 pages, 1921 KiB

Open AccessReview

The Bone Extracellular Matrix as an Ideal Milieu for Cancer Cell Metastases

by Alexus D. Kolb and Karen M. Bussard

Cancers 2019, 11(7), 1020; https://doi.org/10.3390/cancers11071020 - 20 Jul 2019

Cited by 58 | Viewed by 15101

Abstract

Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded [...] Read more.

Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Among the organic components, type I collagen provides the tensile strength of bone. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. Under normal circumstances, two of the main cell types in bone, the osteoblasts and osteoclasts, help to maintain bone homeostasis and remodeling through cellular communication and response to biophysical signals from the ECM. However, under pathological conditions, including osteoporosis and cancer, bone remodeling is dysregulated. Once in the bone matrix, disseminated tumor cells utilize normal products of bone remodeling, such as collagen type I, to fuel cancer cell proliferation and lesion outgrowth. Models to study the complex interactions between the bone matrix and metastatic cancer cells are limited. Advances in understanding the interactions between the bone ECM and bone metastatic cancer cells are necessary in order to both regulate and prevent metastatic cancer cell growth in bone. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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25 pages, 5086 KiB

Open AccessReview

Triple Negative Breast Cancer Profile, from Gene to microRNA, in Relation to Ethnicity

by Ishita Gupta, Rasha M. Sareyeldin, Israa Al-Hashimi, Hamda A. Al-Thawadi, Halema Al Farsi, Semir Vranic and Ala-Eddin Al Moustafa

Cancers 2019, 11(3), 363; https://doi.org/10.3390/cancers11030363 - 13 Mar 2019

Cited by 34 | Viewed by 8576

Abstract

Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack [...] Read more.

Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack of HER-2 expression; this subgroup accounts for ~15% of all breast cancers and exhibits the most aggressive metastatic behavior. Currently, very limited targeted therapies exist for the treatment of patients with TNBCs. On the other hand, it is important to highlight that knowledge of the molecular biology of breast cancer has recently changed the decision-making process regarding the course of cancer therapies. Thus, a number of new techniques, such as gene profiling and sequencing, proteomics, and microRNA analysis have been used to explore human breast carcinogenesis and metastasis including TNBC, which consequently could lead to new therapies. Nevertheless, based on evidence thus far, genomics profiles (gene and miRNA) can differ from one geographic location to another as well as in different ethnic groups. This review provides a comprehensive and updated information on the genomics profile alterations associated with TNBC pathogenesis associated with different ethnic backgrounds. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

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