Rocking the foundations of solid tumor growth by attacking the tumor's blood supply

doi:10.1016/S0167-5699(98)01314-0

Immunology Today

Volume 19, Issue 9, 1 September 1998, Pages 392-394

Immunology Today

https://doi.org/10.1016/S0167-5699(98)01314-0 Get rights and content

Abstract

Deprivation of tumor vascularization is a promising way to prevent tumor outgrowth. Various approaches are under investigation to achieve this, ranging from inhibition of endothelial cell growth or migration to selective tumor vascular targeting of chemotherapeutics. The rapid progress in the field of angiogenesis research, including results presented at a recent meeting³, is discussed here.

Section snippets

Rationale for tumor-vasculature-directed strategies

Angiogenesis provides a growing tumor with a means to metastasize to other tissues as well as to obtain nutrients and oxygen. It is a complex phenomenon comprising cellular activation, proliferation, migration and maturation. After three decades of determined study of the molecular basis of angiogenesis, identification of pro- and anti-angiogenic molecules has now opened a field of research exploiting this knowledge to attack solid tumor growth. An important advantage of the new,

Anti-angiogenic drugs and strategies

A broad array of anti-angiogenic factors and anti-angiogenic strategies interfering at various levels of the angiogenic pathway have been reported[1](Table 1). The fumagillin analog TNP-470/AGM-1470 is used to specifically inhibit endothelial cell proliferation[2], whereas ligands for α_vβ₃ integrin prevent interactions between endothelial cells and the extracellular matrix[3]and thereby inhibit endothelial cell migration and induce endothelial cell apoptosis. Another way to inhibit angiogenesis

VEGF and VEGF receptors

One of the major topics of the conference was the role of vascular endothelial cell growth factor (VEGF) and its receptors in angiogenesis. The pivotal role of VEGF in embryonic development is demonstrated by the fact that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is also important in tumor development. Most human tumors exhibit a high expression of VEGF, and anti-VEGF monoclonal antibodies can block human tumors grown in nude mice[8].

Of mice and men

The results of animal studies have now provided a strong rationale for the development of new therapeutic strategies aimed at interfering with a solid tumor's blood supply. A major issue that remains to be addressed is the size of the tumor burden at initiation of the therapy. In mouse models, tumors are usually grown to a maximal size of ∼0.5 cm diameter. In the clinic, this size is often approximately the limit at which tumors can be detected; a significant number of patients present with much

Acknowledgements

The conference was organized by J. Folkman and M. Klagsbrun, and the American Association for Cancer Research.

References (15)

V. Castronovo et al.
Eur. J. Cancer
(1996)
P.C. Brooks et al.
Cell
(1994)
S. Davis et al.
Cell
(1996)
P.C. Brooks et al.
Cell
(1998)
M. Barinaga
Science
(1997)
M.S. O'Reilly et al.
Nat. Med.
(1996)
T. Boehm et al.
Nature
(1997)

There are more references available in the full text version of this article.

Cited by (43)

Advances and prospects of anginex as a promising anti-angiogenesis and anti-tumor agent
2012, Peptides
Citation Excerpt :
Currently anti-tumor strategies, including surgery, chemotherapy and radiotherapy, often fail in the treatment of solid tumors because of their relapse and metastasis induced by the abundant capillaries. It has been found that interference with angiogenesis or blockade of tumor blood flows are effective ways to treat clinically relevant tumor burdens [34]. Therefore, a combination of tumor-vasculature-directed debulking strategies and conventional tumor-cell-directed drugs or immunotherapy may provide effective treatment for solid tumors.
Anginex, a novel artificial cytokine-like peptide (βpep-25), is designed by using basic folding principles and incorporating short sequences from the β-sheet domains of anti-angiogenic agents, including platelet factor-4 (PF4), interleukin-8 (IL-8), and bactericidal-permeability increasing protein 1 (BP1). Anginex can specially block the adhesion and migration of the angiogenically activated endothelial cells (ECs), leading to apoptosis and ultimately to the inhibition of angiogenesis and tumor growth. In vitro and in vivo studies have proved its inhibitory effects on the formation of new blood vessels and tumor growth even though the mechanism is not clear. The inhibitory effects of anginex can be enhanced when it is applied in combination with other therapies, such as chemotherapy, radiotherapy and other anti-angiogenic agents. The limitations of anginex, including poor stability, short half life, complicated synthesis and low purity, have been conquered by modifying its structure or designing novel compound anginex and recombinant anginex, which makes possible the clinical application of anginex. Here, we summarize the basic and preclinical trials of anginex and discuss the prospects of anginex in clinical application. We come to the conclusion that anginex and compound or recombinant anginex can be used as effective anti-angiogenic agents.
Anti-angiogenesis and anti-tumor effects of AdNT4-anginex
2009, Cancer Letters
Citation Excerpt :
The use of agents that can inhibit angiogenesis has indicated that anti-angiogenic therapy can be a promising therapeutic approach in the future [3,4]. Therefore, targeting activated endothelial cells (ECs) as an anti-tumor treatment is attractive primarily because ECs are more accessible than other cells to pharmacologic agents delivered via the blood, and ECs are genetically stable and are not easily mutated into drug-resistant variants [5,6]. Anginex, a novel artificial β-sheet-forming peptide (βpep-25), has been designed by using a combination approach employing basic folding principles and incorporating short sequences from the β-sheet domains of anti-angiogenic agents including platelet factor-4 (PF4), interleukin-8 (IL-8) and bactericidal-permeability increasing protein1 (BP1) [7–11].
Anginex is a novel artificial peptide that can inhibit angiogenesis. AdNT4-anginex was constructed by inserting the artificial anginex gene into a recombinant adenoviral vector. We demonstrated that AdNT4-anginex inhibited migration of human endothelial cells, angiogenesis and tumor growth in in vitro and in vivo studies. Tumor growth of human H22 hepatoma in mice was inhibited after AdNT4-anginex treatment for 4 weeks, and a significant decrease in tumor size was observed as compared with the control group. Overall, these studies indicate that AdNT4-anginex is an effective anti-tumor agent, and deserves more attention and research.
Angiostatic activity of the antitumor cytokine interleukin-21
2008, Blood
Citation Excerpt :
The process of new blood vessel formation or angiogenesis is essential for tumor growth and metastasis, as it is critical for supply of oxygen and nutrients. Inhibition of angiogenesis is therefore a promising strategy for treatment of cancer.26,27 Several antiangiogenesis compounds have been developed and tested based on their ability to inhibit proangiogenic growth factors, such as vascular endothelial growth factor (VEGF) (SU6668, SU11248, and bevacizumab)28-30 or intervention in signal transduction in endothelial cells directly (TNP-470, endostatin, and anginex).31-34
Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.
Galectins in the tumor endothelium: Opportunities for combined cancer therapy
2007, Blood
Citation Excerpt :
While inflammatory cytokines induce the expression of many adhesion molecules, several proangiogenesis factors released by tumor cells counteract the proinflammatory phenotype of ECs by turning off the “immunogenic switch.” This phenomenon is also referred to as EC anergy, and enables tumors to escape from immunosurveillance.53-55 In the last decade, it has become evident that tumor cells can exploit the expression of galectins to manipulate the immune system (for reviews, see Rabinovich et al56 and Liu et al19).
Galectins are emerging as a family of proteins that play an important role in several steps of tumorigenesis. Evidence is accumulating that galectins are expressed by the tumor endothelium, where they contribute to different steps of tumor progression such as immune escape and metastasis. Recent studies have identified an important role for galectins in tumor angiogenesis. Moreover, it has been shown that galectins in the endothelium can be targeted for therapeutic applications. This opens a window of opportunity for the development of tumor-type independent treatment strategies. This review focuses on the expression of galectins in the tumor endothelium, their contribution to tumor progression, and their application in tumor-type independent cancer therapy.
Radiolabeled biomolecules for early cancer detection and therapy via angiogenesis targeting
2006, Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment
Tumors cannot grow or metastasize without the formation of new blood vessels, i.e. without angiogenesis. A variety of anti-angiogenic agents leading to angiogenesis inhibition are in the clinical trial phase, among which are: (i) molecules which inhibit the action of Vascular Endothelial Growth Factors, VEGF and (ii) molecules which obstruct migration, differentiation and proliferation of endothelial cells, via their binding to receptors of the α_νβ₃ integrins. Certain derivatives of the abovementioned categories, labeled with radionuclides, which emit γ-radiation or β-particles or positrons, have been proposed and are being evaluated as possible radiopharmaceuticals, for the detection and/or treatment of primary or metastatic cancer at an early stage. For the study of angiogenesis the following have been described: (a) antibodies targeting VEGF, labeled with radionuclides emitting β- and/or γ-radiation, which can be applied for the diagnosis and, possibly, for the treatment of cancer, (b) peptide derivatives which contain the amino-acid sequence RGD (Arg-Gly-Asp) and compete for the α_νβ₃ integrins, with the proteins of the stroma. It has been found that these radiolabeled biomolecules localize in tumors and can be used for the visualization and, possibly, for tumor eradication of primary and metastatic cancer. In our laboratory radiolabeling of biomolecules by beta and/or gamma emitters is a principal research goal. In the present work we are presenting our results on the labeling of monoclonal antibodies and peptides with β- and γ-emitting isotopes, as well as on their in vivo evaluation in experimental animal models, by use of specially dedicated imaging devices.
Targeted radionuclide therapy for solid tumors: An overview
2006, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Preclinical studies demonstrating arrest or complete regression of tumors provided support for this hypothesis (74, 75). However, antiangiogenic pharmaceuticals tested in clinical trials thus far have had little effect as single agents (76–79) despite considerable potency in combination with other pharmaceuticals. Combined modality therapy incorporating antiangiogenic agents with RIT offer the potential to target treatment to both tumor and their supporting endothelial cells (66).
Although radioimmunotherapy (RIT) has been effective in non-Hodgkin’s lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET]).