Department of Tumor Biology, Oslo University Hospital--Radiumhospitalet, Oslo, Norway.
Angiogenesis. 2011 Dec;14(4):481-9. doi: 10.1007/s10456-011-9231-3. Epub 2011 Aug 11.
Tumor hypoxia is a common determinant of resistance to cytotoxic therapies and metastatic behavior. In rectal cancer patients receiving preoperative chemoradiotherapy, tyrosine kinase activities in tumors with poor and good treatment responses were found to differ. Given that tyrosine kinase signaling mediates hypoxic tissue adaptation, the present study examined whether tumor kinase activity might also correlate with systemic dissemination of rectal cancer. Immunomagnetic selection of disseminated tumor cells (DTC) from bone marrow aspirates was undertaken in 55 patients with locally advanced rectal cancer. Using peptide arrays with 144 tyrosine kinase substrates, phosphopeptide signatures were generated from patients' baseline tumor biopsies, to study association between DTC and tumor tyrosine kinase activity regulated ex vivo by sunitinib. Disseminated tumor cells were detected in 60% of cases, and these patients had significantly poorer metastasis-free survival than patients without DTC. Phosphorylation of 31 array tyrosine kinase substrates by tumor samples was significantly more strongly inhibited by sunitinib in the DTC-negative patients, with a number of phosphosubstrates representing angiogenic factors. In this cohort of rectal cancer patients, tumor phenotypes defined by a subset of tyrosine kinase activities correlating with weak ex vivo inhibition by sunitinib, was associated with early systemic dissemination.
肿瘤缺氧是导致细胞毒性治疗耐药和转移行为的常见决定因素。在接受术前放化疗的直肠癌患者中，发现治疗反应差和治疗反应好的肿瘤中的酪氨酸激酶活性存在差异。鉴于酪氨酸激酶信号转导介导缺氧组织适应，本研究探讨了肿瘤激酶活性是否也与直肠癌的全身播散相关。对 55 例局部晚期直肠癌患者的骨髓抽吸物进行了弥散性肿瘤细胞（DTC）的免疫磁珠分离。使用包含 144 个酪氨酸激酶底物的肽阵列，从患者的基线肿瘤活检中生成磷酸肽图谱，以研究 DTC 与肿瘤酪氨酸激酶活性之间的关联，该活性通过舒尼替尼在体外进行调节。在 60%的病例中检测到弥散性肿瘤细胞，这些患者的无转移生存明显差于无 DTC 的患者。在 DTC 阴性患者中，肿瘤样本对 31 个阵列酪氨酸激酶底物的磷酸化通过舒尼替尼的抑制明显更强，其中一些磷酸化底物代表了血管生成因子。在这组直肠癌患者中，与舒尼替尼体外抑制作用较弱相关的一组酪氨酸激酶活性定义的肿瘤表型与早期全身播散相关。
