Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.
Bone marrow-derived mesenchymal stromal cells promote survival and drug resistance in tumor cells.
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DOI：
10.1158/1535-7163.mct-13-0400
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发表时间：
2014-04
影响因子：
5.7
通讯作者：
DeClerck YA
中科院分区：
文献类型：
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作者：
Bergfeld SA;Blavier L;DeClerck YA
骨髓间充质基质细胞（BMMSC）具有抗肿瘤活性。在这里，我们假设循环骨髓间充质干细胞被纳入肿瘤并保护肿瘤细胞免受治疗诱导的凋亡。通过小鼠骨髓贴壁细胞表达BMMSC的表型和功能特征，检测其对小鼠4T1乳腺腺癌和LL/2 Lewis肺癌细胞的抗肿瘤活性。BMMSC而非NIH3T3或小鼠皮肤成纤维细胞刺激4T1细胞在3D共培养中的增殖，这些细胞的条件培养基提高了4T1和LL/2细胞在2D培养中的活性。4T1细胞暴露于BMMSC条件培养基中，在低血清浓度（0.5至1%）下，细胞凋亡减少2倍。此外，4T1和LL/2细胞暴露于BMMSC条件培养基中，在治疗浓度的紫杉醇或阿霉素存在下，它们的活力增加。这种影响伴随着caspase-3活性和Annexin V表达的降低。当在随后接受阿霉素治疗的小鼠乳腺脂肪垫中共注射4T1细胞时，BMMSC（而不是成纤维细胞）也抑制了44%的药物诱导的肿瘤细胞凋亡。我们证明了BMMSC可以被4T1和LL/2细胞吸引，但不能被NIH3T3细胞吸引，并且当在4T1荷瘤小鼠中静脉注射时，这些细胞（而不是NIH3T3）在12至18天内在肿瘤中被特异性检测到，并且它们优先定位于侵袭前沿。总的来说，我们的数据确定BMMSC是原发性肿瘤中肿瘤细胞存活和治疗耐药的重要介质。
Bone marrow mesenchymal stromal cells (BMMSC) have anti-tumorigenic activities. Here we hypothesized that circulating BMMSC are incorporated into tumors and protect tumor cells from therapy-induced apoptosis. Adherent cells harvested from murine bone marrow and expressing phenotypic and functional characteristics of BMMSC were tested for their anti-tumor activity against murine 4T1 mammary adenocarcinoma and LL/2 Lewis lung carcinoma cells. BMMSC but not NIH3T3 or murine skin fibroblasts stimulated the expansion of 4T1 cells in 3D co-cultures, and conditioned medium from these cells increased the viability of 4T1 and LL/2 cells in 2D cultures. 4T1 cells exposed to BMMSC conditioned medium exhibited a 2-fold reduction in apoptosis under low serum concentrations (0.5 to 1%). Furthermore, exposure of 4T1 and LL/2 cells to BMMSC conditioned medium increased their viability in the presence of paclitaxel or doxorubicin at therapeutic concentrations. This effect was accompanied by reductions in caspase-3 activity and Annexin V expression. When co-injected with 4T1 cells in the mammary fat pad of mice subsequently treated with doxorubicin, BMMSC (and not fibroblasts) also inhibited drug-induced apoptosis in tumor cells by 44 percent. We demonstrated that BMMSC were attracted by 4T1 and LL/2 cells but not by NIH3T3 cells in vitro and that when injected intravenously in 4T1 tumor bearing mice, these cells (and not NIH 3T3) were specifically detected in tumors within 12 to 18 days where they preferentially localized at the invasive front. Overall, our data identify BMMSC as an important mediator of tumor cell survival and treatment resistance in primary tumors.