Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

Martı́nez, Alfredo; Zudaire, Enrique; Julián, Miguel; Moody, Terry W.; Cuttitta, Frank

doi:10.1038/sj.onc.1208581

Cited by 52 publications

(41 citation statements)

References 41 publications

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“…To explore the possible regulation of angiogenesis by bombesin-like peptides, we used the Matrigel assay of capillary tubulogenesis. We demonstrated that bombesin increases capillary tubulogenesis of pulmonary microvascular endothelial cells cultured alone, consistent with other reports of proangiogenic effects of GRP (49). However, cocultured mesenchymal cells reverse bombesininduced angiogenesis.…”

Section: Discussionsupporting

confidence: 81%

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Subramaniam

Bausch

Twomey

et al. 2007

Am J Respir Crit Care Med

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Rationale: The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, is paradoxically rising despite medical advances. We demonstrated elevated bombesin-like peptide levels in infants that later developed BPD. In the 140-day hyperoxic baboon model of BPD, anti-bombesin antibody 2A11 abrogated lung injury. Objectives: To test the hypothesis that bombesin-like peptides mediate BPD in extremely premature baboons (born at Gestational Day 125 and given oxygen pro re nata [PRN], called the 125-day PRN model), similar to ''modern-day BPD.'' Methods: The 125-day animals were treated with 2A11 on Postnatal Day 1 (P1), P3, and P6. On P14 and P21, lungs were inflation-fixed for histopathologic analyses of alveolarization. Regulation of angiogenesis by bombesin was evaluated using cultured pulmonary microvascular endothelial cells. Measurements and Main Results: In 125-day PRN animals, urine bombesinlike peptide levels at P2-3 are directly correlated with impaired lung function at P14. Gastrin-releasing peptide (the major pulmonary bombesin-like peptide) mRNA was elevated eightfold at P1 and remained high thereafter. At P14, 2A11 reduced alveolar wall thickness and increased the percentage of secondary septa containing endothelial cells. At P21, 2A11-treated 125-day PRN animals had improved alveolarization according to mean linear intercepts and number of branch points per millimeter squared. Bombesin promoted tubulogenesis of cultured pulmonary microvascular endothelial cells, but cocultured fetal lung mesenchymal cells abrogated this effect. Conclusions: Early bombesin-like peptide overproduction in 125-day PRN animals predicted alveolarization defects weeks later. Bombesinlike peptide blockade improved septation, with the greatest effects at P21. This could have implications for preventing BPD in premature infants.Keywords: bombesin; gastrin-releasing peptide; mechanical ventilation; prematurity; antibody treatment Bronchopulmonary dysplasia (BPD) is a chronic lung disease of newborns, often following respiratory distress syndrome. The etiology of BPD remains enigmatic, although it has been associated with multiple factors, including mechanical ventilation, oxygen therapy, infection, inflammatory mediators, and immaturity (1-3). ''Old BPD,'' described by Northway (4), was characterized by airway injury, inflammation, segments of atelectasis alternating with cystic overexpansion, and interstitial fibrosis. Such severe BPD is now less prevalent due to improved medical care. However, BPD is still a major burden in pediatric medicine, paradoxically due to success in improving acute survival. BPD affects approximately 30% of infants weighing less than 1,000 g. ''Modernday BPD,'' occurring in infants less than 30 weeks' gestation, seems to have a different pathophysiology and is characterized by arrested alveolar development and microvascular defects (3,(5)(6)(7)(8).Although many animal models of BPD have been described (9-15), BPD in preterm baboons is most similar to human BPD clinically and path...

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Section: Discussionsupporting

confidence: 81%

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Subramaniam

Bausch

Twomey

et al. 2007

Am J Respir Crit Care Med

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“…1D) had fewer macrophages and neutrophils (PMN) than controls (PBS or MOPC, P < 0.002). MOPC is the ideal isotype (IgG1)-matched negative control for 2A11, controlling for nonspecific protein binding and effects from Fc-gamma receptor binding (40,41).…”

Section: Resultsmentioning

confidence: 99%

“…Direct effects are also likely in airway smooth muscle constriction (21,22), endothelial cell activation and angiogenesis (20,41), and epithelial cell and fibroblast proliferation (6, 31, 52) during remodeling. Indirect effects due to increased cytokine production could occur in parallel, some cytokines being secreted earlier due to direct binding of GRP to GRPR on target cells, amplifying proinflammatory signals via multiple cytokinespecific receptors.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Zhou¹,

Potts

Cuttitta

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans.

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“…Binding of these G-protein-coupled receptors to their respective ligands results in the activation of multiple proliferative signaling cascades [23,24]. GRP also seems to have angiogenic properties, inducing endothelial-cell migration and cord formation in vitro, and promotion of angiogenesis in vivo [25].…”

Section: Gastrin-releasing Peptidementioning

confidence: 99%

Fast, hungry and unstable: finding the Achilles’ heel of small-cell lung cancer

Hann

Rudin

2007

Trends in Molecular Medicine

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Over 95% of patients with small-cell lung cancer (SCLC) die within five years of diagnosis. The standard of care and the dismal prognosis for this disease have not changed significantly over the past 25 years. Some of the characteristics of SCLC that have defined it as a particularly virulent form of cancer -rapid proliferation, excessive metabolic and angiogenic dependence, apoptotic imbalance and genetic instability -are now being pursued as tumor-specific targets for intervention both in preclinical and early phase clinical studies. Here, we summarize areas of ongoing anti-cancer drug development, including classes of agents that target essential pathways regulating proliferation, angiogenesis, apoptotic resistance, chromosomal and protein stability, and cell-cell and cell-matrix interaction.

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Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

Cited by 52 publications

References 41 publications

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

Bombesin-like Peptides Modulate Alveolarization and Angiogenesis in Bronchopulmonary Dysplasia

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Fast, hungry and unstable: finding the Achilles’ heel of small-cell lung cancer

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