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12 pages, 6858 KiB

Open AccessArticle

Abundance of Microvascular Endothelial Cells Is Associated with Response to Chemotherapy and Prognosis in Colorectal Cancer

by Masanori Oshi, Michelle R. Huyser, Lan Le, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2021, 13(6), 1477; https://doi.org/10.3390/cancers13061477 - 23 Mar 2021

Cited by 22 | Viewed by 3071

Abstract

The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the [...] Read more.

The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the xCell algorithm on transcriptome. A total of 1244 CRC patients in discovery and validation cohorts were analyzed. We found that an abundance of mvE cells did not mirror angiogenesis but reflected mature blood vessels because it was significantly associated with a high expression of vascular stability-related genes, including sphingosine-1-phosphate receptor genes and pericytes. Epithelial–mesenchymal transition and myogenesis gene sets were enriched in mvE cell abundant CRC, while mvE cell-less CRC enriched cell proliferation, oxidative phosphorylation, and protein secretion gene sets. mvE cell abundant CRC was associated with infiltration of M2 macrophages, dendritic cells, and less gamma-delta T cells (all p < 0.001), but not with the interferon-γ response. mvE cell abundant CRC was significantly associated with worse patient survival in CRC. Interestingly, mvE cell abundant CRC was significantly associated with a high response rate to chemotherapy (p = 0.012) and worse patient survival for those that did not receive chemotherapy. However, there was no survival difference in patients who underwent chemotherapy. In conclusion, we estimated the abundance of mvE cells using the xCell algorithm on tumor transcriptome finding its association with the number of mature blood vessels in a tumor microenvironment and its ability to predict response to chemotherapy, thereby patient survival in CRC. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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Review

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25 pages, 3151 KiB

Open AccessReview

The Dual Effect of the BMP9–ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement?

by Blanca Ayuso-Íñigo, Lucía Méndez-García, Miguel Pericacho and José M. Muñoz-Félix

Cancers 2021, 13(21), 5412; https://doi.org/10.3390/cancers13215412 - 28 Oct 2021

Cited by 15 | Viewed by 6428

Abstract

The improvement of cancer therapy efficacy, the extension of patient survival and the reduction of adverse side effects are major challenges in cancer research. Targeting blood vessels has been considered a promising strategy in cancer therapy. Since the tumor vasculature is disorganized, leaky [...] Read more.

The improvement of cancer therapy efficacy, the extension of patient survival and the reduction of adverse side effects are major challenges in cancer research. Targeting blood vessels has been considered a promising strategy in cancer therapy. Since the tumor vasculature is disorganized, leaky and triggers immunosuppression and tumor hypoxia, several strategies have been studied to modify tumor vasculature for cancer therapy improvement. Anti-angiogenesis was first described as a mechanism to prevent the formation of new blood vessels and prevent the oxygen supply to tumor cells, showing numerous limitations. Vascular normalization using low doses of anti-angiogenic drugs was purposed to overcome the limitations of anti-angiogenic therapies. Other strategies such as vascular promotion or the induction of high endothelial venules are being studied now to improve cancer therapy. Bone morphogenetic protein 9 (BMP9) exerts a dual effect through the activin receptor-like kinase 1 (ALK1) receptor in blood vessel maturation or activation phase of angiogenesis. Thus, it is an interesting pathway to target in combination with chemotherapies or immunotherapies. This review manuscript explores the effect of the BMP9–ALK1 pathway in tumor angiogenesis and the possible usefulness of targeting this pathway in anti-angiogenesis, vascular normalization or vascular promotion therapies. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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21 pages, 1402 KiB

Open AccessReview

Improved Immunotherapy Efficacy by Vascular Modulation

by Emma L. Newport, Ana Rita Pedrosa, Alexandra Njegic, Kairbaan M. Hodivala-Dilke and José M. Muñoz-Félix

Cancers 2021, 13(20), 5207; https://doi.org/10.3390/cancers13205207 - 17 Oct 2021

Cited by 15 | Viewed by 3348

Abstract

Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development [...] Read more.

Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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40 pages, 3592 KiB

Open AccessReview

New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis

by Irina Larionova, Elena Kazakova, Tatiana Gerashchenko and Julia Kzhyshkowska

Cancers 2021, 13(13), 3253; https://doi.org/10.3390/cancers13133253 - 29 Jun 2021

Cited by 79 | Viewed by 7472

Abstract

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine [...] Read more.

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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54 pages, 7036 KiB

Open AccessReview

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

by Beatrice S. Ludwig, Horst Kessler, Susanne Kossatz and Ute Reuning

Cancers 2021, 13(7), 1711; https://doi.org/10.3390/cancers13071711 - 4 Apr 2021

Cited by 120 | Viewed by 10921

Abstract

Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly [...] Read more.

Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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22 pages, 2803 KiB

Open AccessReview

Hot and Cold Tumors: Is Endoglin (CD105) a Potential Target for Vessel Normalization?

by Claudia Ollauri-Ibáñez, Blanca Ayuso-Íñigo and Miguel Pericacho

Cancers 2021, 13(7), 1552; https://doi.org/10.3390/cancers13071552 - 28 Mar 2021

Cited by 23 | Viewed by 7970

Abstract

Tumors are complex masses formed by malignant but also by normal cells. The interaction between these cells via cytokines, chemokines, growth factors, and enzymes that remodel the extracellular matrix (ECM) constitutes the tumor microenvironment (TME). This TME can be determinant in the prognosis [...] Read more.

Tumors are complex masses formed by malignant but also by normal cells. The interaction between these cells via cytokines, chemokines, growth factors, and enzymes that remodel the extracellular matrix (ECM) constitutes the tumor microenvironment (TME). This TME can be determinant in the prognosis and the response to some treatments such as immunotherapy. Depending on their TME, two types of tumors can be defined: hot tumors, characterized by an immunosupportive TME and a good response to immunotherapy; and cold tumors, which respond poorly to this therapy and are characterized by an immunosuppressive TME. A therapeutic strategy that has been shown to be useful for the conversion of cold tumors into hot tumors is vascular normalization. In this review we propose that endoglin (CD105) may be a useful target of this strategy since it is involved in the three main processes involved in the generation of the TME: angiogenesis, inflammation, and cancer-associated fibroblast (CAF) accumulation. Moreover, the analysis of endoglin expression in tumors, which is already used in the clinic to study the microvascular density and that is associated with worse prognosis, could be used to predict a patient’s response to immunotherapy. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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26 pages, 4839 KiB

Open AccessReview

Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis

by Guillermo Antonio De Paz Linares, Reid Morgan Opperman, Mousumi Majumder and Peeyush K. Lala

Cancers 2021, 13(5), 942; https://doi.org/10.3390/cancers13050942 - 24 Feb 2021

Cited by 19 | Viewed by 5608

Abstract

The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both [...] Read more.

The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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23 pages, 1458 KiB

Open AccessReview

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

by Claudia Ollauri-Ibáñez and Itziar Astigarraga

Cancers 2021, 13(2), 253; https://doi.org/10.3390/cancers13020253 - 12 Jan 2021

Cited by 10 | Viewed by 3254

Abstract

Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop [...] Read more.

Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop the neoplastic cell proliferation and dissemination are needed. Therefore, the inhibition of general processes involved in the growth and behavior of tumors can be a relevant strategy for the development of new cancer therapies. In the case of solid tumors, one of these processes is angiogenesis, essential for tumor growth and generation of metastases. This review summarizes the results obtained with the use of antiangiogenic drugs in the main pediatric malignant solid tumors and also an overview of clinical trials currently underway. It should be noted that due to the rarity and heterogeneity of the different types of pediatric cancer, most studies on antiangiogenic drugs include only a small number of patients or isolated clinical cases, so they are not conclusive and further studies are needed. Full article

(This article belongs to the Special Issue Targeting Blood Vessel Components to Treat Cancer)

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