Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels

Fischer, Christian; Jonckx, Bart; Mazzone, Massimiliano; Zacchigna, Serena; Loges, Sonja; Pattarini, Lucia; Chorianopoulos, Emmanuel; Liesenborghs, Laurens; Koch, Marta; Mol, Maria De; Autiero, Monica; Wyns, Sabine; Plaisance, Stéphane; Moons, Lieve; Rooijen, Nico van; Giacca, Mauro; Stassen, Jean–Marie; Dewerchin, Mieke; Collen, D.; Carmeliet, Peter

doi:10.1016/j.cell.2007.08.038

Cited by 724 publications

(780 citation statements)

References 40 publications

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“…Stimulation of tumour angiogenesis by other pro-angiogenic growth factors in the tumour microenvironment may be one mechanism through which this resistance occurs. Previous work has shown that inhibition of FGF2 or PLGF can overcome acquired resistance to VEGFR2 inhibition in mouse tumour models (Casanovas et al, 2005;Fischer et al, 2007). However, to the best of our knowledge, the direct ability of growth factors to stimulate angiogenesis in human endothelial cells when VEGFR2 is inhibited by sunitinib has not been clearly demonstrated.…”

Section: Discussionmentioning

confidence: 87%

“…In support of this latter concept, FGF2 is upregulated in a mouse tumour model of acquired resistance to DC101 (a VEGFR2 inhibitory antibody) and inhibition of FGF2 in combination with DC101 led to improved anti-tumour responses (Casanovas et al, 2005). Moreover, inhibition of PLGF or PDGF has been reported to enhance the anti-tumour efficacy of VEGF pathway inhibitors in some murine tumour models (Bergers et al, 2003;Fischer et al, 2007;Crawford et al, 2009). Another recent study demonstrated that IL-8 is upregulated in sunitinib-resistant tumour xenografts and that inhibition of IL-8 can re-sensitize these resistant tumours to sunitinib (Huang et al, 2010b).…”

Section: Introductionmentioning

confidence: 94%

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Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 94%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

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“…Anti-Bv8 antibody treatment resulted in a significant decrease of tumor growth and a reduction in CD11b + Gr1 + cell mobilization from the bone marrow. Placenta growth factor (PlGF), a VEGF-family member binding only to VEGFR-1, has been reported to contribute to the recruitment of myeloid cells into the tumor microenvironment (Fischer et al, 2007). Blocking PlGF results in the inhibition of monocyte/macrophage recruitment to tumor sites, reduced tumor angiogenesis and tumor growth, in particular in combination with anti-VEGF therapy (Fischer et al, 2007).…”

Section: Tumor Necrosis Factor (Tnf)mentioning

confidence: 99%

“…Placenta growth factor (PlGF), a VEGF-family member binding only to VEGFR-1, has been reported to contribute to the recruitment of myeloid cells into the tumor microenvironment (Fischer et al, 2007). Blocking PlGF results in the inhibition of monocyte/macrophage recruitment to tumor sites, reduced tumor angiogenesis and tumor growth, in particular in combination with anti-VEGF therapy (Fischer et al, 2007). The role of PlGF in tumor angiogenesis, and its value as potential therapeutic target, however, is matter of controversy (Bais et al, 2010;Van de Veire et al, 2010).…”

Section: Tumor Necrosis Factor (Tnf)mentioning

confidence: 99%

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells

Laurent¹,

Touvrey²,

Botta³

et al. 2011

Int. J. Dev. Biol.

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“…Various studies have reported that TAMs counteract the efficacy of anti-angiogenic agents. For example, TAM depletion with clodronate liposomes synergizes with sorafinib in human hepatocellular carcinoma xenograft models [141] and with the anti-VEGFR2 antibody, DC101, in subcutaneous colon tumors [142] to reduce tumor growth. Synergy also occurs when combining a CSF1R inhibitor with DC101 in another transplantable model [143].…”

Section: Immune Cell Function Following Vascular-targeting Agentsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels

Cited by 724 publications

References 40 publications

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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