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Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 110641

Special Issue Editor

Prof. Dr. Girolamo Ranieri

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Guest Editor
Department of Interventional and Integrated Medical Oncology, National Cancer Research Centre, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
Interests: primary and metastatic liver tumors; pancreatic tumors; colorectal cancers; breast cancers; intra-arterial chemotherapy; chemoembolization; translational oncology angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Angiogenesis is important in tumor growth and progression, and published data suggest that it is a conserved interspecies pathway in animal and human malignancies. Published data strongly indicate that that stromal cells, such as macrophages and mast cells, can stimulate angiogenesis operating in the tumor microenvironments. These cells are able to secrete proangiogenic factors, and, from them, non classical factors, such as tryptase, are now recognized to play a significant role. The mechanisms of stromal cell activation, that in turn can induce the release pro-angiogenic substances, are an important area of study for the identification of novel targets to inhibit neovascularization. In the same manner, the inhibition of angiogenesis-targeting tryptase and other non-classical pro-angiogenic factors is a field of research that aims to expand the repertoire of oncological therapies. Research in comparative tumor angiogenesis has been developed over the last decade, resulting in a better biological understanding of tumor and stromal cell interaction, with the identification of novel tyrosine kinase inhibitors, such as masitinib, which it is now ongoing in human clinical trials. From a therapeutic point of view, novel combinations employing angiogenesis inhibitors with chemotherapy, and with physical therapies, such us radiotherapy and hyperthermia, are now ongoing.

In this Special Issue, we welcome your contributions in the form of original research and review articles on all aspects of “Angiogenesis and Anti-Angiogenesis in Oncology”.

Dr. Girolamo Ranieri MD
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor angiogenesis
  • mast cells
  • macrophages
  • non classical proangiogenic factors
  • tumor animal model of angiogenesis
  • human tumor
  • angiogenesis inhibitors
  • chemotherapy
  • radiotherapy
  • oncological hyperthermia

Published Papers (16 papers)

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Editorial

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3 pages, 154 KiB  
Editorial
Biological Basis of Tumor Angiogenesis and Therapeutic Intervention: Past, Present, and Future
by Girolamo Ranieri
Int. J. Mol. Sci. 2018, 19(6), 1655; https://doi.org/10.3390/ijms19061655 - 04 Jun 2018
Cited by 5 | Viewed by 2264
Abstract
n/a Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)

Research

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12 pages, 9872 KiB  
Article
The Adenosine A3 Receptor Regulates Differentiation of Glioblastoma Stem-Like Cells to Endothelial Cells under Hypoxia
by René Rocha, Ángelo Torres, Karina Ojeda, Daniel Uribe, Dellis Rocha, José Erices, Ignacio Niechi, Pamela Ehrenfeld, Rody San Martín and Claudia Quezada
Int. J. Mol. Sci. 2018, 19(4), 1228; https://doi.org/10.3390/ijms19041228 - 18 Apr 2018
Cited by 32 | Viewed by 4330
Abstract
Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A3 adenosine [...] Read more.
Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A3 adenosine receptor (A3AR). Moreover, GSCs potentiates the persistent neovascularization in GBM. The aim of this study was to determine if A3AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to Endothelial Cells (ECs) under hypoxia. We evaluated the expression of endothelial cell markers (CD31, CD34, CD144, and vWF) by fluorescence-activated cell sorting (FACS), and vascular endothelial growth factor (VEGF) secretion by ELISA using MRS1220 (A3AR antagonist) under hypoxia. We validate our results using U87MG-GSCs A3AR knockout (GSCsA3-KO). The effect of MRS1220 on blood vessel formation was evaluated in vivo using a subcutaneous GSCs-tumor model. GSCs increased extracellular adenosine production and A3AR expression under hypoxia. Hypoxia also increased the percentage of GSCs positive for endothelial cell markers and VEGF secretion, which was in turn prevented when using MRS1220 and in GSCsA3-KO. Finally, in vivo treatment with MRS1220 reduced tumor size and blood vessel formation. Blockade of A3AR decreases the differentiation of GSCs to ECs under hypoxia and in vivo blood vessel formation. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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Graphical abstract

14 pages, 4249 KiB  
Article
Tumor-Associated Macrophages and Mast Cells Positive to Tryptase Are Correlated with Angiogenesis in Surgically-Treated Gastric Cancer Patients
by Giuseppe Sammarco, Cosmo Damiano Gadaleta, Valeria Zuccalà, Emre Albayrak, Rosa Patruno, Pietro Milella, Rosario Sacco, Michele Ammendola and Girolamo Ranieri
Int. J. Mol. Sci. 2018, 19(4), 1176; https://doi.org/10.3390/ijms19041176 - 12 Apr 2018
Cited by 33 | Viewed by 3421
Abstract
Mast cells and macrophages can play a role in tumor angiogenesis by stimulating microvascular density (MVD). The density of mast cells positive to tryptase (MCDPT), tumor-associated macrophages (TAMs), and MVD were evaluated in a series of 86 gastric cancer (GC) tissue samples from [...] Read more.
Mast cells and macrophages can play a role in tumor angiogenesis by stimulating microvascular density (MVD). The density of mast cells positive to tryptase (MCDPT), tumor-associated macrophages (TAMs), and MVD were evaluated in a series of 86 gastric cancer (GC) tissue samples from patients who had undergone potential curative surgery. MCDPT, TAMs, and MVD were assessed in tumor tissue (TT) and in adjacent normal tissue (ANT) by immunohistochemistry and image analysis. Each of the above parameters was correlated with the others and, in particular for TT, with important clinico-pathological features. In TT, a significant correlation between MCDPT, TAMs, and MVD was found by Pearson t-test analysis (p ranged from 0.01 to 0.02). No correlation to the clinico-pathological features was found. A significant difference in terms of mean MCDPT, TAMs, and MVD between TT and ANT was found (p ranged from 0.001 to 0.002). Obtained data suggest MCDPT, TAMs, and MVD increased from ANT to TT. Interestingly, MCDPT and TAMs are linked in the tumor microenvironment and they play a role in GC angiogenesis in a synergistic manner. The assessment of the combination of MCDPT and TAMs could represent a surrogate marker of angiogenesis and could be evaluated as a target of novel anti-angiogenic therapies in GC patients. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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8709 KiB  
Article
Mast Cells Interact with Endothelial Cells to Accelerate In Vitro Angiogenesis
by Devandir Antonio De Souza Junior, Vivian Marino Mazucato, Ana Carolina Santana, Constance Oliver and Maria Celia Jamur
Int. J. Mol. Sci. 2017, 18(12), 2674; https://doi.org/10.3390/ijms18122674 - 13 Dec 2017
Cited by 19 | Viewed by 5028
Abstract
Angiogenesis is a complex process that involves interactions between endothelial cells and various other cell types as well as the tissue microenvironment. Several previous studies have demonstrated that mast cells accumulate at angiogenic sites. In spite of the evidence suggesting a relationship between [...] Read more.
Angiogenesis is a complex process that involves interactions between endothelial cells and various other cell types as well as the tissue microenvironment. Several previous studies have demonstrated that mast cells accumulate at angiogenic sites. In spite of the evidence suggesting a relationship between mast cells and angiogenesis, the association of mast cells and endothelial cells remains poorly understood. The present study aims to investigate the relationship between mast cells and endothelial cells during in vitro angiogenesis. When endothelial cells were co-cultured with mast cells, angiogenesis was stimulated. Furthermore, there was direct intercellular communication via gap junctions between the two cell types. In addition, the presence of mast cells stimulated endothelial cells to release angiogenic factors. Moreover, conditioned medium from the co-cultures also stimulated in vitro angiogenesis. The results from this investigation demonstrate that mast cells have both direct and indirect proangiogenic effects and provide new insights into the role of mast cells in angiogenesis. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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Graphical abstract

2385 KiB  
Article
Bevacizumab-Based Chemotherapy Combined with Regional Deep Capacitive Hyperthermia in Metastatic Cancer Patients: A Pilot Study
by Girolamo Ranieri, Cristina Ferrari, Alessandra Di Palo, Ilaria Marech, Mariangela Porcelli, Gianmarco Falagario, Fabiana Ritrovato, Luigi Ramunni, Margherita Fanelli, Giuseppe Rubini and Cosmo Damiano Gadaleta
Int. J. Mol. Sci. 2017, 18(7), 1458; https://doi.org/10.3390/ijms18071458 - 06 Jul 2017
Cited by 13 | Viewed by 4347
Abstract
As an angiogenesis inhibitor, bevacizumab has been investigated in combination with different chemotherapeutic agents, achieving an established role for metastatic cancer treatment. However, potential synergic anti-angiogenic effects of hyperthermia have not tested to date in literature. The aim of our study was to [...] Read more.
As an angiogenesis inhibitor, bevacizumab has been investigated in combination with different chemotherapeutic agents, achieving an established role for metastatic cancer treatment. However, potential synergic anti-angiogenic effects of hyperthermia have not tested to date in literature. The aim of our study was to analyze efficacy, safety, and survival of anti-angiogenic-based chemotherapy associated to regional deep capacitive hyperthermia (HT) in metastatic cancer patients. Twenty-three patients with metastatic colorectal (n = 16), ovarian (n = 5), and breast (n = 2) cancer were treated with HT in addition to a standard bevacizumab-based chemotherapy regimen. Treatment response assessment was performed, according to the modified Response Evaluation Criteria for Solid Tumors (mRECIST), at 80 days (timepoint-1) and at 160 days (timepoint-2) after therapy. Disease Response Rate (DRR), considered as the proportion of patients who had the best response rating (complete response (CR), partial response (PR), or stable disease (SD)), was assessed at timepoint-1 and timepoint-2. Chi-squared for linear trend test was performed to evaluated the association between response groups (R/NR) and the number of previous treatment (none, 1, 2, 3), number of chemotherapy cycles (<6, 6, 12, >12), number of hyperthermia sessions (<12, 12, 24, >24), and lines of chemotherapy (I, II). Survival curves were estimated by Kaplan-Meier method. DRR was 85.7% and 72.2% at timepoint-1 and timepoint-2, respectively. HT was well tolerated without additional adverse effects on chemotherapy-related toxicity. Chi-squared for linear trend test demonstrated that the percentage of responders grew in relation to the number of chemotherapy cycles (p = 0.015) and to number of HT sessions (p < 0.001) performed. Both overall survival (OS) and time to progression (TTP) were influenced by the number of chemotherapy cycles (p < 0.001) and HT sessions (p < 0.001) performed. Our preliminary data, that need to be confirmed in larger studies, suggest that the combined treatment of bevacizumab-based chemotherapy with HT has a favorable tumor response, is feasible and well tolerated, and offers a potentially promising option for metastatic cancer patients. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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17157 KiB  
Article
Bevacizumab for Patients with Recurrent Gliomas Presenting with a Gliomatosis Cerebri Growth Pattern
by Michael C. Burger, Iris C. Mildenberger, Marlies Wagner, Michel Mittelbronn, Joachim P. Steinbach and Oliver Bähr
Int. J. Mol. Sci. 2017, 18(4), 726; https://doi.org/10.3390/ijms18040726 - 29 Mar 2017
Cited by 7 | Viewed by 4006
Abstract
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing [...] Read more.
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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Graphical abstract

Review

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25 pages, 1499 KiB  
Review
“Vessels in the Storm”: Searching for Prognostic and Predictive Angiogenic Factors in Colorectal Cancer
by Adriano Angelucci, Simona Delle Monache, Alessio Cortellini, Monica Di Padova and Corrado Ficorella
Int. J. Mol. Sci. 2018, 19(1), 299; https://doi.org/10.3390/ijms19010299 - 19 Jan 2018
Cited by 28 | Viewed by 4967
Abstract
High expectations are placed upon anti-angiogenic compounds for metastatic colorectal cancer (mCRC), the first malignancy for which such type of treatment has been approved. Indeed, clinical trials have confirmed that targeting the formation of new vessels can improve in many cases clinical outcomes [...] Read more.
High expectations are placed upon anti-angiogenic compounds for metastatic colorectal cancer (mCRC), the first malignancy for which such type of treatment has been approved. Indeed, clinical trials have confirmed that targeting the formation of new vessels can improve in many cases clinical outcomes of mCRC patients. However, current anti-angiogenic drugs are far from obtaining the desirable or expected curative results. Many are the factors probably involved in such disappointing results, but particular attention is currently focused on the validation of biomarkers able to improve the direction of treatment protocols. Because clinical studies have clearly demonstrated that serum or tissue concentration of some angiogenic factors is associated with the evolution of the disease of mCRC patients, they are currently explored as potential biomarkers of prognosis and of tumor response to therapy. However, the complex biology underlying CRC -induced angiogenesis is a hurdle in finding rapid solutions. The aim of this review was to explore molecular mechanisms that determine the formation of tumor-associated vessels during CRC progression, and to discuss the potential role of angiogenic factors as diagnostic, prognostic and predictive biomarkers in CRC. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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635 KiB  
Review
Angiogenesis and Anti-Angiogenic Therapy in Gastric Cancer
by Henrik Nienhüser and Thomas Schmidt
Int. J. Mol. Sci. 2018, 19(1), 43; https://doi.org/10.3390/ijms19010043 - 23 Dec 2017
Cited by 73 | Viewed by 7582
Abstract
Gastric cancer is one of the most frequent malignancies worldwide. Despite improvements in diagnosis and therapy, the overall prognosis remains poor. In the last decade, several anti-angiogenic drugs for cancer treatment have been approved and lately also introduced to gastric cancer treatment. While [...] Read more.
Gastric cancer is one of the most frequent malignancies worldwide. Despite improvements in diagnosis and therapy, the overall prognosis remains poor. In the last decade, several anti-angiogenic drugs for cancer treatment have been approved and lately also introduced to gastric cancer treatment. While the initial trials focused only on unresectable or metastatic cancer, anti-angiogenic treatment is now also investigated in the perioperative and neoadjuvant setting. In this review, an overview of the role of angiogenesis and angiogenic factors in gastric cancer as well as anti-angiogenic treatment of gastric cancer is provided. Findings from in vitro and animal studies are summarized and put in a context with translational data on angiogenesis in gastric cancer. The most important angiogenic factors and their effect in gastric cancer are highlighted and clinical trials including anti-angiogenic drugs are discussed. Finally, an outlook of biomarkers for predicting response to anti-angiogenic treatment is presented, the ongoing trials on this topic are discussed and current challenges of anti-angiogenic therapy are outlined. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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1276 KiB  
Review
A Combination of Immune Checkpoint Inhibition with Metronomic Chemotherapy as a Way of Targeting Therapy-Resistant Cancer Cells
by Irina Kareva
Int. J. Mol. Sci. 2017, 18(10), 2134; https://doi.org/10.3390/ijms18102134 - 13 Oct 2017
Cited by 50 | Viewed by 7088
Abstract
Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by [...] Read more.
Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by immune cell death induced by cytotoxic treatments. High-frequency low-dose (also known as metronomic) chemotherapy can help improve the activity of CTLs by providing sufficient stimulation for cytotoxic immune cells without excessive depletion. Additionally, therapy-induced removal of tumor cells that compete for shared nutrients may also facilitate tumor infiltration by CTLs, further improving prognosis. Metronomic chemotherapy can also decrease the number of immunosuppressive cells in the tumor microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Immune checkpoint inhibition can further augment anti-tumor immune responses by maintaining T cells in an activated state. Combining immune checkpoint inhibition with metronomic administration of chemotherapeutic drugs may create a synergistic effect that augments anti-tumor immune responses and clears metabolic competition. This would allow immune-mediated elimination of therapy-resistant cancer cells, an effect that may be unattainable by using either therapeutic modality alone. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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417 KiB  
Review
Angiogenesis Inhibitors in NSCLC
by Anna Manzo, Agnese Montanino, Guido Carillio, Raffaele Costanzo, Claudia Sandomenico, Nicola Normanno, Maria Carmela Piccirillo, Gennaro Daniele, Francesco Perrone, Gaetano Rocco and Alessandro Morabito
Int. J. Mol. Sci. 2017, 18(10), 2021; https://doi.org/10.3390/ijms18102021 - 21 Sep 2017
Cited by 75 | Viewed by 7455
Abstract
Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC [...] Read more.
Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer (NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857, p = 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (p = 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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1067 KiB  
Review
Biological Pathways Involved in Tumor Angiogenesis and Bevacizumab Based Anti-Angiogenic Therapy with Special References to Ovarian Cancer
by Vera Loizzi, Vittoria Del Vecchio, Giulio Gargano, Maria De Liso, Anila Kardashi, Emanuele Naglieri, Leonardo Resta, Ettore Cicinelli and Gennaro Cormio
Int. J. Mol. Sci. 2017, 18(9), 1967; https://doi.org/10.3390/ijms18091967 - 14 Sep 2017
Cited by 78 | Viewed by 18903
Abstract
The creation of new blood vessels from existing ones, which is a mechanism called “angiogenesis”, is essential in cancer to supply cancerous growth. Moreover, the development and the progression of the tumor and its metastases are the result of an efficient vascular response. [...] Read more.
The creation of new blood vessels from existing ones, which is a mechanism called “angiogenesis”, is essential in cancer to supply cancerous growth. Moreover, the development and the progression of the tumor and its metastases are the result of an efficient vascular response. Cancer cells release and activate different angiogenic growth factors and their receptors in the tumor microenvironment to promote the angiogenic process. The most important pro-angiogenic factor is the “Vascular Endothelial Growth Factor” (VEGF) because of its mitogen activity on vascular endothelium. Bevacizumab is a monoclonal antibody that obstructs the binding of circulating vascular endothelial growth factor to its receptors and has been approved for the treatment of primary and recurrent ovarian cancer but also for many other solid tumors. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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1763 KiB  
Review
Multimodality Imaging in Tumor Angiogenesis: Present Status and Perspectives
by Artor Niccoli Asabella, Alessandra Di Palo, Corinna Altini, Cristina Ferrari and Giuseppe Rubini
Int. J. Mol. Sci. 2017, 18(9), 1864; https://doi.org/10.3390/ijms18091864 - 28 Aug 2017
Cited by 35 | Viewed by 4858
Abstract
Angiogenesis is a complex biological process that plays a central role in progression of tumor growth and metastasis. It led to a search for antiangiogenic molecules, and to design antiangiogenic strategies for cancer treatment. Noninvasive molecular imaging, such as positron emission tomography (PET) [...] Read more.
Angiogenesis is a complex biological process that plays a central role in progression of tumor growth and metastasis. It led to a search for antiangiogenic molecules, and to design antiangiogenic strategies for cancer treatment. Noninvasive molecular imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), could be useful for lesion detection, to select patients likely to respond to antiangiogenic therapies, to confirm successful targeting, and dose optimization. Additionally, nuclear imaging techniques could also aid in the development of new angiogenesis-targeted drugs and their validation. Angiogenesis imaging can be categorized as targeted at three major cell types: (I) non-endothelial cell targets, (II) endothelial cell targets, and (III) extracellular matrix proteins and matrix proteases. Even if radiopharmaceuticals studying the metabolism and hypoxia can be also used for the study of angiogenesis, many of the agents used in nuclear imaging for this purpose are yet to be investigated. The purpose of this review is to describe the role of molecular imaging in tumor angiogenesis, highlighting the advances in this field. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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807 KiB  
Review
A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy
by Deok-Hoon Kong, Mi Ra Kim, Ji Hye Jang, Hee-Jun Na and Sukmook Lee
Int. J. Mol. Sci. 2017, 18(8), 1786; https://doi.org/10.3390/ijms18081786 - 17 Aug 2017
Cited by 127 | Viewed by 11469
Abstract
Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling [...] Read more.
Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis. However, despite the clinical efficacy of bevacizumab, its significant side effects and drug resistance have raised concerns necessitating the identification of novel drug targets and development of novel therapeutics to combat tumor angiogenesis. This review will highlight the role and relevance of VEGF and other potential therapeutic targets and their receptors in angiogenesis. Simultaneously, we will also cover the current status of monoclonal antibodies being developed to target these candidates for cancer therapy. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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567 KiB  
Review
Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma
by Mathias Alrø Fichtner Bendtsen, Daniela Grimm, Johann Bauer, Markus Wehland, Petra Wise, Nils E. Magnusson, Manfred Infanger and Marcus Krüger
Int. J. Mol. Sci. 2017, 18(8), 1736; https://doi.org/10.3390/ijms18081736 - 10 Aug 2017
Cited by 22 | Viewed by 7939
Abstract
Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus [...] Read more.
Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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563 KiB  
Review
Effects and Side Effects of Using Sorafenib and Sunitinib in the Treatment of Metastatic Renal Cell Carcinoma
by Caroline Randrup Hansen, Daniela Grimm, Johann Bauer, Markus Wehland and Nils E. Magnusson
Int. J. Mol. Sci. 2017, 18(2), 461; https://doi.org/10.3390/ijms18020461 - 21 Feb 2017
Cited by 65 | Viewed by 7785
Abstract
In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line [...] Read more.
In recent years, targeted therapies have proven beneficial in terms of progression-free survival (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC). The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are included in international clinical guidelines as first-line and second-line therapy in mRCC. Hypertension is an adverse effect of these drugs and the degree of hypertension associates with the anti-tumour effect. Studies have compared newer targeted drugs to sorafenib and sunitinib in terms of PFS, OS, quality of life and safety profiles. Phase III studies presented promising response rates and acceptable safety profiles of axitinib and tivozanib compared to sorafenib, and a phase II study reported greater efficacy using a combination of bevacizumab and IFN-α compared to sunitinib. Treatment with nintedanib exhibited a notably low prevalence of hypertension compared to sunitinib. The use of sorafenib and sunitinib are challenged by new drugs, but do not appear likely to be substituted in the near future. To clarify whether newer targeted drugs should replace sorafenib and sunitinib, more research is needed. This manuscript reviews the current utility and adverse effects of sorafenib and sunitinib and newer targeted therapies in the treatment of mRCC. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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Review
Bone Niches, Hematopoietic Stem Cells, and Vessel Formation
by Roberto Tamma and Domenico Ribatti
Int. J. Mol. Sci. 2017, 18(1), 151; https://doi.org/10.3390/ijms18010151 - 13 Jan 2017
Cited by 66 | Viewed by 8079
Abstract
Bone marrow (BM) is a source of hematopoietic stem cells (HSCs). HSCs are localized in both the endosteum, in the so-called endosteal niche, and close to thin-walled and fenestrated sinusoidal vessel in the center of BM, in the so-called vascular niche. HSCs give [...] Read more.
Bone marrow (BM) is a source of hematopoietic stem cells (HSCs). HSCs are localized in both the endosteum, in the so-called endosteal niche, and close to thin-walled and fenestrated sinusoidal vessel in the center of BM, in the so-called vascular niche. HSCs give rise to all types of mature blood cells through a process finely controlled by numerous signals emerging from the bone marrow niches where HSCs reside. This review will focus on the description of the role of BM niches in the control of the fate of HSCs and will also highlight the role of the BM niches in the regulation of vasculogenesis and angiogenesis. Moreover, alterations of the signals in niche microenvironment are involved in many aspects of tumor progression and vascularization and further knowledge could provide the basis for the development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Angiogenesis and Anti-Angiogenesis in Oncology: From Bench to Translational Research and Bedside Investigation)
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