Interleukin-8 Mediates Resistance to Antiangiogenic Agent Sunitinib in Renal Cell Carcinoma

Huang, Dan; Ding, Yan; Zhou, Ming; Rini, Brian I.; Petillo, David; Qian, Chao Nan; Kahnoski, Richard J.; Futreal, P. Andrew; Furge, Kyle A.; Teh, Bin Tean

doi:10.1158/0008-5472.can-09-3965

Cited by 379 publications

(288 citation statements)

References 25 publications

(32 reference statements)

Supporting

Mentioning

270

Contrasting

Order By: Relevance

“…Table 3 attempts to score the benefits and adverse effects of the different treatments used in our study. The best score (7) was obtained with anti-CXCL8 treatment, which is consistent with the results of Huang et al (2010) and Kopetz et al (2010), whereas the worst score (À6) was assigned to treatment with BVZ twice weekly or to treatment with paclitaxel/BVZ/anti-CXCL8. Although treatment with anti-CXCL8 is apparently the best, VEGFxxxb and CXCL7, two markers involved in the prognosis of RCC, were not affected by anti-CXCL8 antibodies.…”

Section: Discussionsupporting

confidence: 81%

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

et al. 2011

View full text Add to dashboard Cite

The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/ CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-j, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.

show abstract

Section: Discussionsupporting

confidence: 81%

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

et al. 2011

View full text Add to dashboard Cite

show abstract

“…This may reflect a limitation of our in vitro screening approach and we cannot exclude the possibility that some of the angiogenic factors screened may indeed have a role in resistance to sunitinib in vivo. Of note, a recent study demonstrated a role for IL-8 in mediating resistance to sunitinib in vivo (Huang et al, 2010b), whereas our screen did not reveal a role for IL-8. It is likely that tumour-specific microenvironmental effects, which are not recapitulated in our assay, may permit certain growth factors to influence the response of endothelial cells to sunitinib in vivo.…”

Section: Discussioncontrasting

confidence: 79%

“…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: 99%

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

“…For instance, in patients with advanced clear cell renal cell carcinoma (ccRCC), most patients develop sunitinib resistance and progressive disease after about 1 year of treatment [32]. That is actually due to the vascular resistance to the anti-angiogenic effect of sunitinib, through activation of alternative proangiogenic pathways [33].…”

Section: Strategies Of Cancer Cell Resistance For Drugsmentioning

confidence: 99%