Takeuchi Yoshinori, Fujino Yasuhito, Watanabe Manabu, Nakagawa Takayuki, Ohno Koichi, Sasaki Nobuo, Sugano Sumio, Tsujimoto Hajime
Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
J Vet Med Sci. 2011 Oct;73(10):1295-302. doi: 10.1292/jvms.11-0093. Epub 2011 Jun 7.
Options of systemic treatment for canine MCT have been still limited and most canine cases with MCTs eventually undergo relapses even after achievement of a remission. Thus additional therapies are required to establish for the tumor. To identify the novel candidate therapeutic targets for canine MCT, the mRNA expression and phosphorylation statuses of several receptor or non-receptor kinases as well as the inhibitory effect of 95 specific inhibitors on the growth were assessed in three canine MCT cell lines (HRMC, VIMC1 and CMMC1). Among the 14 targets, the mRNAs of 11, 7 and 7 kinases were amplified in HRMC, VIMC1 and CMMC1, respectively. The mRNAs of VEGFR3, PDGFRα, SRC, YES, LCK and FYN were detected in all cell lines. The phosphorylation of 12, 8 and 7 kinases was observed by using specific antibody arrays in HRMC, VIMC1 and CMMC1, respectively. DTK, EPHB6, AMPKα1, CREB, STAT5a and STAT5b were phosphorylated in all cell lines. The 10, 9 and 17 inhibitors exhibited the biological activity against the growth of HRMC, VIMC1 and CMMC1, respectively. Only three inhibitors such as SB218078 (for Chk1), PDGF RTK inhibitor IV (for PDGFR) and radicicol (for Hsp90) suppressed the growth of all three cell lines. The present study indicated that several kinases, such as Chk1, PDGFR and Hsp90, could be used as therapeutic targets in the treatment for canine MCT. Further studies and clinical trials are warranted to apply the inhibitors for the treatment of the tumor.
犬肥大细胞瘤全身治疗的选择仍然有限，大多数患有肥大细胞瘤的犬病例即使在缓解后最终仍会复发。因此，需要为该肿瘤建立额外的治疗方法。为了确定犬肥大细胞瘤的新型候选治疗靶点，在三种犬肥大细胞瘤细胞系（HRMC、VIMC1和CMMC1）中评估了几种受体或非受体激酶的mRNA表达和磷酸化状态，以及95种特异性抑制剂对其生长的抑制作用。在14个靶点中，HRMC、VIMC1和CMMC1中分别扩增出11、7和7种激酶的mRNA。所有细胞系中均检测到VEGFR3、PDGFRα、SRC、YES、LCK和FYN的mRNA。分别在HRMC、VIMC1和CMMC1中使用特异性抗体阵列观察到12、8和7种激酶的磷酸化。DTK、EPHB6、AMPKα1、CREB、STAT5a和STAT5b在所有细胞系中均被磷酸化。10、9和17种抑制剂分别对HRMC、VIMC1和CMMC1的生长具有生物学活性。只有三种抑制剂，如SB218078（针对Chk1）、PDGF RTK抑制剂IV（针对PDGFR）和radicicol（针对Hsp90）抑制了所有三种细胞系的生长。本研究表明，Chk1、PDGFR和Hsp90等几种激酶可作为犬肥大细胞瘤治疗的靶点。有必要进行进一步的研究和临床试验，以应用这些抑制剂治疗该肿瘤。
