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Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.

Shibasaki N, Yamasaki T, Kanno T, Arakaki R, Sakamoto H, Utsunomiya N, Inoue T, Tsuruyama T, Nakamura E, Ogawa O, Kamba T - PLoS ONE (2015)

Bottom Line: Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells.Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo.To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

ABSTRACT
Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

No MeSH data available.


Related in: MedlinePlus

KURC1 tumors develop resistance to sunitinib but KURC2 remained sensitive.(A) Hematoxylin and eosin (H&E) staining of an original RCC surgical specimen and xenograft KURC1 and KURC2 tumor tissue. Scale bar, 50 μm. (B) The sequential changes of KURC1 and KURC2 xenograft tumors treated with sunitinib or vehicle only and (C) Left: KURC1 tumor volume at 4 weeks later from passage (sunitinib treatment day 0). Right: The sequential changes of KURC1 sunitinib 5th and vehicle 5th. KURC1 repeatedly treated with sunitinib or vehicle 5th. Each time point represents the mean ± SE of tumor volume in each group. Day 0 is the first day of sunitinib administration at 4 weeks after transplantation. The difference in tumor size between sunitinib 5th group and vehicle 5th group in KURC1 was not statistically significant using two-way repeated ANOVA. Arrowed bars indicate the periods of sunitinib administration. ▼ indicates the time point when tumors were resected.
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pone.0130980.g001: KURC1 tumors develop resistance to sunitinib but KURC2 remained sensitive.(A) Hematoxylin and eosin (H&E) staining of an original RCC surgical specimen and xenograft KURC1 and KURC2 tumor tissue. Scale bar, 50 μm. (B) The sequential changes of KURC1 and KURC2 xenograft tumors treated with sunitinib or vehicle only and (C) Left: KURC1 tumor volume at 4 weeks later from passage (sunitinib treatment day 0). Right: The sequential changes of KURC1 sunitinib 5th and vehicle 5th. KURC1 repeatedly treated with sunitinib or vehicle 5th. Each time point represents the mean ± SE of tumor volume in each group. Day 0 is the first day of sunitinib administration at 4 weeks after transplantation. The difference in tumor size between sunitinib 5th group and vehicle 5th group in KURC1 was not statistically significant using two-way repeated ANOVA. Arrowed bars indicate the periods of sunitinib administration. ▼ indicates the time point when tumors were resected.

Mentions: Two cohorts of primary xenografts were established and stably engrafted following three or more passages in vivo. We named them as primary xenograft KURC1 and KURC2. Histopathological diagnosis of primary tumor was clear cell type RCC of Grade 2 > 3, pT2N0M0 for KURC1 and clear cell type RCC, G3, pT3aN0M1 for KURC2. Each xenograft mostly recaptured the histopathological features of original tumors in tumor grade and architecture (Fig 1A). We have found necrosis in the center of tumors and N-cadherin was strongly expressed in both xenograft tumors (S1 Fig).


Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.

Shibasaki N, Yamasaki T, Kanno T, Arakaki R, Sakamoto H, Utsunomiya N, Inoue T, Tsuruyama T, Nakamura E, Ogawa O, Kamba T - PLoS ONE (2015)

KURC1 tumors develop resistance to sunitinib but KURC2 remained sensitive.(A) Hematoxylin and eosin (H&E) staining of an original RCC surgical specimen and xenograft KURC1 and KURC2 tumor tissue. Scale bar, 50 μm. (B) The sequential changes of KURC1 and KURC2 xenograft tumors treated with sunitinib or vehicle only and (C) Left: KURC1 tumor volume at 4 weeks later from passage (sunitinib treatment day 0). Right: The sequential changes of KURC1 sunitinib 5th and vehicle 5th. KURC1 repeatedly treated with sunitinib or vehicle 5th. Each time point represents the mean ± SE of tumor volume in each group. Day 0 is the first day of sunitinib administration at 4 weeks after transplantation. The difference in tumor size between sunitinib 5th group and vehicle 5th group in KURC1 was not statistically significant using two-way repeated ANOVA. Arrowed bars indicate the periods of sunitinib administration. ▼ indicates the time point when tumors were resected.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482605&req=5

pone.0130980.g001: KURC1 tumors develop resistance to sunitinib but KURC2 remained sensitive.(A) Hematoxylin and eosin (H&E) staining of an original RCC surgical specimen and xenograft KURC1 and KURC2 tumor tissue. Scale bar, 50 μm. (B) The sequential changes of KURC1 and KURC2 xenograft tumors treated with sunitinib or vehicle only and (C) Left: KURC1 tumor volume at 4 weeks later from passage (sunitinib treatment day 0). Right: The sequential changes of KURC1 sunitinib 5th and vehicle 5th. KURC1 repeatedly treated with sunitinib or vehicle 5th. Each time point represents the mean ± SE of tumor volume in each group. Day 0 is the first day of sunitinib administration at 4 weeks after transplantation. The difference in tumor size between sunitinib 5th group and vehicle 5th group in KURC1 was not statistically significant using two-way repeated ANOVA. Arrowed bars indicate the periods of sunitinib administration. ▼ indicates the time point when tumors were resected.
Mentions: Two cohorts of primary xenografts were established and stably engrafted following three or more passages in vivo. We named them as primary xenograft KURC1 and KURC2. Histopathological diagnosis of primary tumor was clear cell type RCC of Grade 2 > 3, pT2N0M0 for KURC1 and clear cell type RCC, G3, pT3aN0M1 for KURC2. Each xenograft mostly recaptured the histopathological features of original tumors in tumor grade and architecture (Fig 1A). We have found necrosis in the center of tumors and N-cadherin was strongly expressed in both xenograft tumors (S1 Fig).

Bottom Line: Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells.Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo.To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

ABSTRACT
Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

No MeSH data available.


Related in: MedlinePlus