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12 pages, 3228 KiB

Open AccessArticle

P2X Purinergic Receptors Are Multisensory Detectors for Micro-Environmental Stimuli That Control Migration of Tumoral Endothelium

by Giorgia Scarpellino, Tullio Genova, Elisa Quarta, Carla Distasi, Marianna Dionisi, Alessandra Fiorio Pla and Luca Munaron

Cancers 2022, 14(11), 2743; https://doi.org/10.3390/cancers14112743 - 31 May 2022

Cited by 6 | Viewed by 1612

Abstract

The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn²⁺) and calcium (Ca²⁺). We previously reported the ability of some purinergic agonists to exert an anti-migratory [...] Read more.

The tumoral microenvironment often displays peculiar features, including accumulation of extracellular ATP, hypoxia, low pH-acidosis, as well as an imbalance in zinc (Zn²⁺) and calcium (Ca²⁺). We previously reported the ability of some purinergic agonists to exert an anti-migratory activity on tumor-derived human endothelial cells (TEC) only when applied at a high concentration. They also trigger calcium signals associated with release from intracellular stores and calcium entry from the external medium. Here, we provide evidence that high concentrations of BzATP (100 µM), a potent agonist of P2X receptors, decrease migration in TEC from different tumors, but not in normal microvascular ECs (HMEC). The same agonist evokes a calcium increase in TEC from the breast and kidney, as well as in HMEC, but not in TEC from the prostate, suggesting that the intracellular pathways responsible for the P2X-induced impairment of TEC migration could vary among different tumors. The calcium signal is mainly due to a long-lasting calcium entry from outside and is strictly dependent on the presence of the receptor occupancy. Low pH, as well as high extracellular Zn²⁺ and Ca²⁺, interfere with the response, a distinctive feature typically found in some P2X purinergic receptors. This study reveals that a BzATP-sensitive pathway impairs the migration of endothelial cells from different tumors through mechanisms finely tuned by environmental factors. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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15 pages, 2943 KiB

Open AccessArticle

Is Sphingosine-1-Phosphate a Regulator of Tumor Vascular Functionality?

by Manale Karam, Annette Ives and Christian Auclair

Cancers 2022, 14(5), 1302; https://doi.org/10.3390/cancers14051302 - 03 Mar 2022

Cited by 3 | Viewed by 1558

Abstract

Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which [...] Read more.

Increasing evidence indicates that tumor vasculature normalization could be an appropriate strategy to increase therapies’ efficacy in solid tumors by decreasing hypoxia and improving drug delivery. We searched for a novel approach that reduces hypoxia and enhances chemotherapy efficacy in pancreatic adenocarcinoma which is characterized by disrupted blood vasculature associated with poor patient survival. Clinical significance of plasma levels of the angiogenic lipid sphingosine-1-phosphate (S1P) was assessed at baseline in 175 patients. High plasma S1P concentration was found to be a favorable prognostic/predictive marker in advanced/metastatic pancreatic adenocarcinoma patients treated by gemcitabine alone but not in patients receiving a combination gemcitabine and PDGFR-inhibitor. In pancreatic adenocarcinoma PDX models, oral administration of an S1P lyase inhibitor (LX2931) significantly increased plasma S1P levels, decreased tumor expression of the hypoxia marker (CA IX), and enhanced chemotherapy efficacy when combined with gemcitabine treatment. The direct effect of S1P on tumor oxygenation was assessed by administration of S1P onto tumor-grafted CAM model and measuring intra-tumoral pO2 using a tissue oxygen monitor. S1P increased pO2 in a tumor-CAM model. Thus, increasing plasma S1P is a promising strategy to decrease tumor hypoxia and enhance therapy efficacy in solid tumors. S1P may act as a tumor vasculature normalizer. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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21 pages, 3588 KiB

Open AccessArticle

Superoxide Dismutase-3 Downregulates Laminin α5 Expression in Tumor Endothelial Cells via the Inhibition of Nuclear Factor Kappa B Signaling

by Lorena Carmona-Rodríguez, Diego Martínez-Rey, Paula Martín-González, Mónica Franch, Lydia Sorokin, Emilia Mira and Santos Mañes

Cancers 2022, 14(5), 1226; https://doi.org/10.3390/cancers14051226 - 26 Feb 2022

Cited by 1 | Viewed by 2354

Abstract

The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced [...] Read more.

The balance between laminin isoforms containing the α5 or the α4 chain in the endothelial basement membrane determines the site of leukocyte diapedesis under inflammatory conditions. Extracellular superoxide dismutase (SOD3) induces laminin α4 expression in tumor blood vessels, which is associated with enhanced intratumor T cell infiltration in primary human cancers. We show now that SOD3 overexpression in neoplastic and endothelial cells (ECs) reduces laminin α5 in tumor blood vessels. SOD3 represses the laminin α5 gene (LAMA5), but LAMA5 expression is not changed in SOD1-overexpressing cells. Transcriptomic analyses revealed SOD3 overexpression to change the transcription of 1682 genes in ECs, with the canonical and non-canonical NF-κB pathways as the major SOD3 targets. Indeed, SOD3 reduced the transcription of well-known NF-κB target genes as well as NF-κB-driven promoter activity in ECs stimulated with tumor necrosis factor (TNF)-α, an NF-κB signaling inducer. SOD3 inhibited the phosphorylation and degradation of IκBα (nuclear factor of the kappa light polypeptide gene enhancer in B-cells inhibitor alpha), an NF-κB inhibitor. Finally, TNF-α was found to be a transcriptional activator of LAMA5 but not of LAMA4; LAMA5 induction was prevented by SOD3. In conclusion, SOD3 is a major regulator of laminin balance in the basement membrane of tumor ECs, with potential implications for immune cell infiltration into tumors. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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22 pages, 67825 KiB

Open AccessArticle

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

by Yihang Guo, Honghong Wang, Jeni L. Gerberich, Samuel O. Odutola, Amanda K. Charlton-Sevcik, Maoping Li, Rajendra P. Tanpure, Justin K. Tidmore, Mary Lynn Trawick, Kevin G. Pinney, Ralph P. Mason and Li Liu

Cancers 2021, 13(19), 4769; https://doi.org/10.3390/cancers13194769 - 24 Sep 2021

Cited by 6 | Viewed by 2891

Abstract

The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic [...] Read more.

The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO₂) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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25 pages, 11520 KiB

Open AccessArticle

Picturing Breast Cancer Brain Metastasis Development to Unravel Molecular Players and Cellular Crosstalk

by Inês Figueira, Sofia Galego, Tânia Custódio-Santos, Raquel Vicente, Kinga Molnár, Janos Haskó, Rui Malhó, Mafalda Videira, Imola Wilhelm, István Krizbai and Maria Alexandra Brito

Cancers 2021, 13(4), 910; https://doi.org/10.3390/cancers13040910 - 22 Feb 2021

Cited by 12 | Viewed by 3573

Abstract

With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood–brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors [...] Read more.

With breast cancer (BC) therapy improvements, the appearance of brain metastases has been increasing, representing a life-threatening condition. Brain metastasis formation involves BC cell (BCC) extravasation across the blood–brain barrier (BBB) and brain colonization by unclear mechanisms. We aimed to disclose the actors involved in BC brain metastasis formation, focusing on BCCs’ phenotype, growth factor expression, and signaling pathway activation, correlating with BBB alterations and intercellular communication. Hippocampi of female mice inoculated with 4T1 BCCs were examined over time by hematoxylin-eosin, immunohistochemistry and immunofluorescence. Well-established metastases were observed at seven days, increasing thereafter. BCCs entering brain parenchyma presented mesenchymal, migratory, and proliferative features; however, with time, they increasingly expressed epithelial markers, reflecting a mesenchymal–epithelial transition. BCCs also expressed platelet-derived growth factor-B, β₄ integrin, and focal adhesion kinase, suggesting autocrine and/or paracrine regulation with adhesion signaling activation, while balance between Rac1 and RhoA was associated with the motility status. Intercellular communication via gap junctions was clear among BCCs, and between BCCs and endothelial cells. Thrombin accumulation, junctional protein impairment, and vesicular proteins increase reflect BBB alterations related with extravasation. Expression of plasmalemma vesicle-associated protein was increased in BCCs, along with augmented vascularization, whereas pericyte contraction indicated mural cells’ activation. Our results provide further understanding of BC brain metastasis formation, disclosing potential therapeutic targets. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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Review

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22 pages, 1395 KiB

Open AccessReview

Angiogenesis: A Pivotal Therapeutic Target in the Drug Development of Gynecologic Cancers

by Lawrence Kasherman, Shiru (Lucy) Liu, Katherine Karakasis and Stephanie Lheureux

Cancers 2022, 14(5), 1122; https://doi.org/10.3390/cancers14051122 - 22 Feb 2022

Cited by 5 | Viewed by 2206

Abstract

Since the discovery of angiogenesis and its relevance to the tumorigenesis of gynecologic malignancies, a number of therapeutic agents have been developed over the last decade, some of which have become standard treatments in combination with other therapies. Limited clinical activity has been [...] Read more.

Since the discovery of angiogenesis and its relevance to the tumorigenesis of gynecologic malignancies, a number of therapeutic agents have been developed over the last decade, some of which have become standard treatments in combination with other therapies. Limited clinical activity has been demonstrated with anti-angiogenic monotherapies, and ongoing trials are focused on combination strategies with cytotoxic agents, immunotherapies and other targeted treatments. This article reviews the science behind angiogenesis within the context of gynecologic cancers, the evidence supporting the targeting of these pathways and future directions in clinical trials. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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12 pages, 631 KiB

Open AccessReview

Nucleic Acid Sensing in the Tumor Vasculature

by Adrian M. Baris, Eugenia Fraile-Bethencourt and Sudarshan Anand

Cancers 2021, 13(17), 4452; https://doi.org/10.3390/cancers13174452 - 03 Sep 2021

Cited by 7 | Viewed by 3226

Abstract

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain [...] Read more.

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors, such as cGAS-STING, in combination with immunotherapies. In this review, we present a case for targeting nucleic acid-sensing pathways within the tumor vasculature to invigorate tumor-immune responses. We introduce two specific nucleic acid sensors—the DNA sensor TREX1 and the RNA sensor RIG-I—and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid-sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment by co-opting both vascular and immune cell types. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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19 pages, 1329 KiB

Open AccessEditor’s ChoiceReview

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

by Kathy Matuszewska, Madison Pereira, Duncan Petrik, Jack Lawler and Jim Petrik

Cancers 2021, 13(17), 4444; https://doi.org/10.3390/cancers13174444 - 03 Sep 2021

Cited by 41 | Viewed by 5686

Abstract

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the [...] Read more.

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area. Full article

(This article belongs to the Special Issue Tumor Vasculature – Biological Insights and Therapeutic Opportunities)

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