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Targeting Tumor Angiogenesis and Metastasis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 26429

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Special Issue Editor

Dr. Minah Kim

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Guest Editor

Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
Interests: angiogenesis; metastasis; immunotherapy; drug resistance; tumor microenvironment

Special Issue Information

Dear Colleagues,

Tumor angiogenesis and vascular remodeling regulate not only primary tumor growth but also tumor cell metastasis to distant organs by establishing a premetastatic niche. These processes have provided a rationale for the development and application of anti-angiogenic drugs in the treatment of many advanced cancers, although the emergence of resistance to anti-angiogenic drugs has limited their therapeutic success. Emerging evidence also suggests that vascular normalization promotes immunostimulation, and vice versa. As immunosuppression is associated with resistance to current immunotherapies, targeting vascular abnormalities in the tumor microenvironment in combination with immunotherapy has been proposed as an ideal approach for the treatment of cancer patients. Therefore, understanding the mechanisms by which vascular abnormalities in the tumor microenvironment contribute to tumor progression, metastasis, and immunosuppression is important to target drug resistance in current anti-angiogenic and immunotherapies.

In this Special Issue, we welcome contributions of research or review articles on the targeting of tumor angiogenesis and metastasis to improve current anti-angiogenic and immunotherapies in cancer.

Dr. Minah Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

Angiogenesis
Vascular remodeling
Metastasis
Immunotherapies
Anti-angiogenic therapies
Drug resistance
Tumor microenvironment

Published Papers (7 papers)

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Research

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16 pages, 2661 KiB

Open AccessArticle

Intra-Tumoral Angiogenesis Is Associated with Inflammation, Immune Reaction and Metastatic Recurrence in Breast Cancer

by Masanori Oshi, Stephanie Newman, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Masayuki Nagahashi and Kazuaki Takabe

Int. J. Mol. Sci. 2020, 21(18), 6708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186708 - 13 Sep 2020

Cited by 64 | Viewed by 3990

Abstract

Angiogenesis is one of the hallmarks of cancer. We hypothesized that intra-tumoral angiogenesis correlates with inflammation and metastasis in breast cancer patients. To test this hypothesis, we generated an angiogenesis pathway score using gene set variation analysis and analyzed the tumor transcriptome of 3999 breast cancer patients from The Cancer Genome Atlas Breast Cancer (TCGA-BRCA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE20194, GSE25066, GSE32646, and GSE2034 cohorts. We found that the score correlated with expression of various angiogenesis-, vascular stability-, and sphingosine-1-phosphate (S1P)-related genes. Surprisingly, the angiogenesis score was not associated with breast cancer subtype, Nottingham pathological grade, clinical stage, response to neoadjuvant chemotherapy, or patient survival. However, a high score was associated with a low fraction of both favorable and unfavorable immune cell infiltrations except for dendritic cell and M2 macrophage, and with Leukocyte Fraction, Tumor Infiltrating Lymphocyte Regional Fraction and Lymphocyte Infiltration Signature scores. High-score tumors had significant enrichment for unfavorable inflammation-related gene sets (interleukin (IL)6, and tumor necrosis factor (TNF)α- and TGFβ-signaling), as well as metastasis-related gene sets (epithelial mesenchymal transition, and Hedgehog-, Notch-, and WNT-signaling). High score was significantly associated with metastatic recurrence particularly to brain and bone. In conclusion, using the angiogenesis pathway score, we found that intra-tumoral angiogenesis is associated with immune reaction, inflammation and metastasis-related pathways, and metastatic recurrence in breast cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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39 pages, 8478 KiB

Open AccessArticle

Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

by Olga Kurmyshkina, Pavel Kovchur, Ludmila Schegoleva and Tatyana Volkova

Int. J. Mol. Sci. 2020, 21(18), 6515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186515 - 06 Sep 2020

Cited by 6 | Viewed by 4022

Abstract

The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early dissemination to cancer cells. Recent research has revealed substantial interdependence between these processes at the molecular level as they rely on common signaling networks. Of great interest are the molecular mechanisms of (lymph-)angiogenesis and EMT associated with the earliest stages of transition from intraepithelial development to invasive growth, as they could provide the source of potentially valuable tools for targeting tumor metastasis. However, in the case of early-stage cervical cancer, the players of (lymph-)angiogenesis and EMT processes still remain substantially uncharacterized. In this study, we used RNA sequencing to compare transcriptomes of HPV(+) preinvasive neoplastic lesions and early-stage invasive carcinoma of the cervix and to identify (lymph-)angiogenesis- and EMT-related genes and pathways that may underlie early acquisition of invasive phenotype and metastatic properties by cervical cancer cells. Second, we applied flow cytometric analysis to evaluate the expression of three key lymphangiogenesis/EMT markers (VEGFR3, MET, and SLUG) in epithelial cells derived from enzymatically treated tissue specimens. Overall, among 201 differentially expressed genes, a considerable number of (lymph-)angiogenesis and EMT regulatory factors were identified, including genes encoding cytokines, growth factor receptors, transcription factors, and adhesion molecules. Pathway analysis confirmed enrichment for angiogenesis, epithelial differentiation, and cell guidance pathways at transition from intraepithelial neoplasia to invasive carcinoma and suggested immune-regulatory/inflammatory pathways to be implicated in initiation of invasive growth of cervical cancer. Flow cytometry showed cell phenotype-specific expression pattern for VEGFR3, MET, and SLUG and revealed correlation with the amount of tumor-infiltrating lymphocytes at the early stages of cervical cancer progression. Taken together, these results extend our understanding of driving forces of angiogenesis and metastasis in HPV-associated cervical cancer and may be useful for developing new treatments. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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23 pages, 6706 KiB

Open AccessArticle

Bioinformatics and Molecular Insights to Anti-Metastasis Activity of Triethylene Glycol Derivatives

by Vidhi Malik, Sukant Garg, Sajal Afzal, Jaspreet Kaur Dhanjal, Chae-Ok Yun, Sunil C. Kaul, Durai Sundar and Renu Wadhwa

Int. J. Mol. Sci. 2020, 21(15), 5463; https://doi.org/10.3390/ijms21155463 - 30 Jul 2020

Cited by 6 | Viewed by 3529

Abstract

The anti-metastatic and anti-angiogenic activities of triethylene glycol derivatives have been reported. In this study, we investigated their molecular mechanism(s) using bioinformatics and experimental tools. By molecular dynamics analysis, we found that (i) triethylene glycol dimethacrylate (TD-10) and tetraethylene glycol dimethacrylate (TD-11) can act as inhibitors of the catalytic domain of matrix metalloproteinases (MMP-2, MMP-7 and MMP-9) by binding to the S1’ pocket of MMP-2 and MMP-9 and the catalytic Zn ion binding site of MMP-7, and that (ii) TD-11 can cause local disruption of the secondary structure of vascular endothelial growth factor A (VEGFA) dimer and exhibit stable interaction at the binding interface of VEGFA receptor R1 complex. Cell-culture-based in vitro experiments showed anti-metastatic phenotypes as seen in migration and invasion assays in cancer cells by both TD-10 and TD-11. Underlying biochemical evidence revealed downregulation of VEGF and MMPs at the protein level; MMP-9 was also downregulated at the transcriptional level. By molecular analyses, we demonstrate that TD-10 and TD-11 target stress chaperone mortalin at the transcription and translational level, yielding decreased expression of vimentin, fibronectin and hnRNP-K, and increase in extracellular matrix (ECM) proteins (collagen IV and E-cadherin) endorsing reversal of epithelial–mesenchymal transition (EMT) signaling. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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13 pages, 2096 KiB

Open AccessArticle

EPA and DHA Fatty Acids Induce a Remodeling of Tumor Vasculature and Potentiate Docetaxel Activity

by Caroline Goupille, Sophie Vibet, Philippe G. Frank and Karine Mahéo

Int. J. Mol. Sci. 2020, 21(14), 4965; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144965 - 14 Jul 2020

Cited by 13 | Viewed by 2319

Abstract

n-3 long chain Polyunsaturated Fatty Acids (n-3 LCPUFA) have been shown to improve the efficacy of conventional chemotherapies used for breast cancer treatment. In addition to their reported ability to increase the chemosensitivity of cancer cells, we hypothesized that n-3 LCPUFA could induce a remodeling of the vascular network in mammary tumors. A contrast-enhanced ultrasound method was used to monitor the vascular architecture during docetaxel treatment of mammary tumors in rats fed either a control or an n-3 LCPUFA-enriched diet (docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA)). The vascular network was remodeled in favor of smaller vessels (microvascularization), which represented 54% of the vasculature in n-3 LCPUFA tumors but only 26% in control tumors after 2 weeks of chemotherapy. Importantly, vascularization changes occurred both before and during docetaxel treatment. The density of smaller vessels quantified before chemotherapy was correlated with improved tumor size reduction by docetaxel treatment. Furthermore, transcript levels of the angiogenesis-specific genes epiregulin and amphiregulin were reduced by ~4.5- and twofold in tumors obtained from rats fed an n-3 LCPUFA-enriched diet compared to those of rats fed a control diet, respectively. Their expression levels were negatively correlated with tumor regression after chemotherapy. Taken together, this preclinical data strengthen the potential usefulness of n-3 LCPUFA as a complementary clinical strategy to improve drug efficiency via remodeling of the tumor vasculature. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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19 pages, 2543 KiB

Open AccessArticle

Overcoming Intrinsic Doxorubicin Resistance in Melanoma by Anti-Angiogenic and Anti-Metastatic Effects of Liposomal Prednisolone Phosphate on Tumor Microenvironment

by Emilia Licarete, Valentin Florian Rauca, Lavinia Luput, Denise Drotar, Ioana Stejerean, Laura Patras, Bogdan Dume, Vlad Alexandru Toma, Alina Porfire, Claudia Gherman, Alina Sesarman and Manuela Banciu

Int. J. Mol. Sci. 2020, 21(8), 2968; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082968 - 23 Apr 2020

Cited by 18 | Viewed by 3586

Abstract

Regardless of recent progress, melanoma is very difficult to treat, mainly due to the drug resistance modulated by tumor cells as well as by the tumor microenvironment (TME). Among the immune cells recruited at the tumor site, tumor associated macrophages (TAMs) are the most abundant, promoting important tumorigenic processes: angiogenesis, inflammation and invasiveness. Furthermore, it has been shown that TAMs are involved in mediating the drug resistance of melanoma cells. Thus, in the present study, we used liposomal formulation of prednisolone disodium phosphate (LCL-PLP) to inhibit the protumor function of TAMs with the aim to sensitize the melanoma cells to the cytotoxic drug doxorubicin (DOX) to which human melanoma has intrinsic resistance. Consequently, we evaluated the in vivo effects of the concomitant administration of LCL-PLP and liposomal formulation of DOX (LCL-DOX) on B16.F10 melanoma growth and on the production of key molecular markers for tumor development. Our results demonstrated that the concomitant administration of LCL-PLP and LCL-DOX induced a strong inhibition of tumor growth, primarily by inhibiting TAMs-mediated angiogenesis as well as the tumor production of MMP-2 and AP-1. Moreover, our data suggested that the combined therapy also affected TME as the number of infiltrated macrophages in melanoma microenvironment was reduced significantly. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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13 pages, 2410 KiB

Open AccessArticle

DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression

by Tsung-Chieh Lin

Int. J. Mol. Sci. 2020, 21(8), 2881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082881 - 20 Apr 2020

Cited by 6 | Viewed by 2629

Abstract

DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, DDX3X’s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to DDX3X. The results suggest that DDX3X is epigenetically repressed in tumor tissue and that lower DDX3X is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by DDX3X. Furthermore, SPINK1 and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with DDX3X in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low DDX3X. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3X_low/SPINK1_high/metallothionein_high axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low DDX3X expression levels. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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Review

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20 pages, 1299 KiB

Open AccessReview

The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer

by Alessandra Leong and Minah Kim

Int. J. Mol. Sci. 2020, 21(22), 8689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228689 - 18 Nov 2020

Cited by 35 | Viewed by 5731

Abstract

Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy. Further, emerging evidence suggests a fundamental link between vascular abnormalities and tumor immune evasion, supporting the rationale for combination strategies of immunotherapy with antiangiogenic drugs. In this review, we discuss the recent mechanistic and clinical advances in targeting angiopoietin signaling, focusing on ANG2 inhibition, to enhance therapeutic efficacy of antiangiogenic and ICI therapies. In short, we propose that a better mechanistic understanding of ANG2-mediated vascular changes will provide insight into the significance of ANG2 in treatment response and resistance to current antiangiogenic and ICI therapies. These advances will ultimately improve therapeutic modalities for cancer treatment. Full article

(This article belongs to the Special Issue Targeting Tumor Angiogenesis and Metastasis)

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