Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.

By O. Casanovas, D. Hicklin, G. Bergers, D. Hanahan. Cancer Cell, 2005

1,655 citations recorded by the source corpus.

Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition.

Subfields: Cancer Research, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/2929d8cdc24d9297b51568054ea0036ed84ca446

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Rakesh K. Jain
2. N. Ferrara
3. D. Hanahan
4. Peter Carmeliet
5. M. Shibuya
6. G. Bergers
7. H. Gerber
8. Daniel Chen

In Molecular Biology

1. Rakesh K. Jain
2. N. Ferrara
3. Peter Carmeliet
4. D. Hanahan
5. M. Shibuya
6. J. Joyce
7. D. Duda
8. G. Bergers

In Neurology

1. M. Shibuya
2. D. Hanahan
3. N. Ferrara
4. G. Bergers
5. Rakesh K. Jain

Citations in the corpus

• NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES (2011, neutral): “Aside from the molecules discussed in this review, other possible mediators of the escape process include bFGF (49, 311) and stromal-derived factor-1 (SDF1 ) (76, 306).”
• Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. (2011, background): “Of note, enhanced expression of Fgf2, Sdf1, and Hgf has been previously associated with tumor resistance to various antiangiogenic or radiation treatments (Casanovas et al., 2005; Kozin et al., 2010; Shojaei et al., 2010).”
• Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells (2007, background): “Tumor cell–intrinsic or treatment-induced expression of alternative pro-angiogenic factors during tumor progression might be implicate”
• Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. (2007, background): “Treatment with a single antiangiogenic agent may lead to acquired drug resistance based on an escape mechanism via induction of an angiogenic rescue program; for instance, FGF is upregulated after aVEGFR-2 treatment (Casanovas et al., 2005).”
• Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. (2011, neutral): “Constipation 12 (14) 12 (14) 0 16 (20) 15 (18) 1 (1)”
• Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation (2017, methodology): “Thus, we can evaluate true response and relapse phases in a single model (17, 19, 26).”
• Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. (2009, methodology): “Tumor-bearing immunocompromised RIP1-Tag2 mice treated with DC101 for a relatively brief period of 1 week had reduced tumor vasculature and volume compared to control age-matched untreated animals, as described previously (Figure 1A and data not shown; Casanovas et al., 2005).”
• Rapid vascular regrowth in tumors after reversal of VEGF inhibition. (2006, background): “Studies of RIP-Tag2 tumors have shown significant contributions of bone marrow progenitor cells to mural cells of the vasculature and to myofibroblasts in the stroma, but no contribution to the endothelium of tumor vessels has been described (63, 64).”
• AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. (2007, background): “These findings were also confirmed recently in oncogene-induced insulinomas (Casanovas et al., 2005).”
• Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment. (2006, background): “For instance, recent experiments have addressed the role of hypoxia in promoting aggressive behavior and invasive morphology (Casanovas et al., 2005; Erler et al., 2006; Pennacchietti et al., 2003) but did not examine the clonal or phenotypic composition of resulting tumors.”