br Patients and Methods br Results br Discussion Gjerdrum et
Patients and Methods
Discussion Gjerdrum et al showed that Axl lipoxygenase is required to maintain the mesenchymal-like invasiveness of metastatic breast carcinoma cells, but Axl knockdown has no effect on the cell proliferation of MDA-MB-231 cells. Mackiewicz et al also showed that down-regulation of Axl expression results in decreased cell motility but has no effect on the cell viability of MDA-MB-231 cells. These studies suggest that Axl is linked to cell invasion or migration without having any effect on cell proliferation or viability. On the other hand, Vuoriluoto et al showed that vimentin expression is necessary for EMT-associated migration, and its knockdown causes a decrease in genes linked to breast cancer cell migration and invasiveness, such as Axl. The authors also showed that silencing of vimentin decreased Axl protein levels, and knocking down Axl had no effect on vimentin expression. The relationships between vimentin and Axl expression have been reported in cell lines; however, less is known about these relationships in clinical samples. Therefore, we conducted this study and demonstrated for the first time that the coexistence of vimentin and Axl-high expression correlated with prognosis in clinical breast cancer samples. On the other hand, in this study, 78% of cases of expression of Axl-high expression were vimentin negative, and 22% of cases of expression of Axl-high expression were vimentin positive. Vimentin has been shown to be required for induction of Axl expression in a previous study. Our data showed that Axl expression might be regulated by not only vimentin but also by the other factor. With regard to the factor associated with Axl expression, further study is needed. Overexpression or activation of Axl has been reported in several drug-resistant cancer cell lines.6, 23, 24, 25, 26 Up-regulation of Axl by EMT induction has been shown to mediate acquired resistance in lapatinib-resistant, HER-2–positive breast tumor cells. In this study, coexistence of vimentin-positive and Axl-high expression was also significantly associated with poor prognosis in HER-2–positive and TNBC patients. In addition, all TNBC patients with Axl-high expression died within about 2 years after recurrence. These results suggest that Axl expression might be associated with the resistance to chemotherapy. Further investigation in a larger number of these patients is needed. On the other hand, down-regulation of Axl showed the reverse of EMT in mesenchymal cell lines, reduction of tumor growth, down-regulation of NF-κB pathway, and restoration of sensitivity to chemotherapy. Combination of Axl inhibition and antimitotic agents showed a synergistic effect in cancer cells that demonstrated tyrosine kinase inhibitor resistance, but Axl inhibition alone had no effect on the acquired resistance to tyrosine kinase inhibitor.
Acknowledgments This work was supported by Ministry of Education, Culture, Sports, Science, and Technology grant-in-aid 15H05792. We are grateful to Naoko Katakura and Yuko Kubota for valuable technical assistance.
Introduction Kidney cancer is the seventh most common cancer in men and tenth most common cancer in woman worldwide . Renal cell carcinoma (RCC) is responsible for 90% of all kidney cancer, and approximately 80% of these are clear cell tumors, with the other 20% being less common RCC subtypes, like papillary and chromophobe tumors , . In Brazil kidney cancer is the 15th cancer in incidence with approximately 3,700 new cases per year responsible for more than 2,000 deaths per year . Most clear cell cancer is sporadic while hereditary autosomal dominant syndromes are described as responsible for approximately 2%–3% of all RCCs, being the Von Hippel Lindau (VHL) disease the most common form , . VHL disease is caused by a germline mutation in the VHL gene that predisposes to clear cell RCC and other proliferative vascular tumors . VHL gene plays an important role, not only in hereditary but also in sporadic clear cell cancer, since inactivation of VHL leads to elevated levels of the transcription factor hypoxia-inducible factor 1α (HIF-1α) and subsequent overexpression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which promote tumor angiogenesis. Bi-allelic VHL gene alterations can occur through VHL gene mutations, hypermethylation of VHL gene promoter and loss of heterozygosity, which characterizes more than 80% of sporadic cases .