骨髓脂肪细胞在肺癌骨转移中的作用及机制研究

Bone metastasis is very common in lung cancer patients, resulting in a significant negative impact on both morbidity and survival. Adipocytes are a cell population largely located in the human bone marrow cavity. Depending on specific demands, bone marrow adipocytes may acquire different functions based on their local environment, including regulating hematopoiesis, affecting bone formation and transforming into functional osteoblasts. Prostate cancer and breast cancer preferentially metastasises to the bone. Recent studies demonstrated that bone marrow adipocytes is a potent stimulator of the bone metastasis of prostate cancer and breast cancer. Our preliminary experiment showed that there was a significantly difference in expression of adipocytokines among bone marrow, subcutaneous and omental adipose tissue. We found that the level of ICAM-1and FGF21 secreted by bone marrow adipocytes was significantly elevated. Adipocyte and lung cancer cell co-culture significantly enhanced invasion and metastasis of lung cancer cells, accompanied by significant increases in cytoplasmic lipid droplets in These effects were accompanied by significant increases in cytoplasmic lipid droplets. Given all these consideration, we speculated that adipocyte might induced the lung cancer bone metastasis, and the bone metastasis and metabolism of lung cancer associated with the increased serum ICAM-1and FGF21 levels. Therefore, we intended to further identify the effect of bone marrow adipocyte on the bone metastasis of lung cancer and elucidate the potential molecular mechanism, by using bone marrow adipocyte and lung cancer co-culture model, animal model of lung cancer bone metastasis and clinical specimens. Our study could not only contribute to understanding about the mechanism of metabolism and bone metastasis of lung cancer, but also provide new ideas and therapeutic direction for lung cancer..

骨是肺癌最常见的远处转移部位之一，骨转移的发生常预示患者生活质量下降和生存期的缩短。近期研究发现：骨髓脂肪细胞与骨转移高发的乳腺癌、前列腺癌的骨转移关系密切。课题组前期研究发现：骨髓脂肪细胞分泌的因子与皮下和大网膜脂肪细胞分泌的因子存在显著差异，ICAM-1和FGF21表达显著升高；肺癌细胞和骨髓脂肪细胞共培养显著增强肺癌细胞的侵袭和转移能力，肺癌细胞脂滴明显增多。由此课题组推测：骨髓脂肪细胞是影响肺癌细胞骨转移倾向的重要因素，ICAM-1和FGF21可能与肺癌的骨转移和代谢密切相关。因此，课题组拟利用骨髓脂肪细胞与肺癌细胞共培养模型、肺癌骨转移动物模型和临床标本，通过体内、外研究，进一步明确骨髓脂肪细胞对肺癌细胞骨转移的作用和主要机制。研究结果不仅有利于我们进一步认识肺癌骨转移机制，同时对开发新的防治肺癌骨转移药物，提高肺癌骨转移防治效果具有重要意义。

骨是肺癌最常见的远处转移部位之一，近期研究发现：骨髓脂肪细胞与骨转移高发的乳腺癌、前列腺癌的骨转移关系密切。有部分研究推测脂肪细胞可通过影响癌细胞的代谢而促进多种恶性肿瘤的发生与发展。为证实骨髓脂肪细胞在肺癌骨转移中的作用及机制，课题组将3T3-L1前脂肪细胞诱导为成熟脂肪细胞，应用Transwell小室将前脂肪细胞或成熟脂肪细胞分别与A549细胞间接共培养。通过显微镜成像、油红O染色、MTT实验、平板克隆形成实验、划痕实验以及Transwell迁移观察肺癌细胞的形态、增殖、迁移及侵袭能力的改变。通过比色分析法测定细胞糖脂代谢相关指标，探讨了脂肪细胞对肺癌A549细胞生物学行为的影响。结果显示，与成熟脂肪细胞共培养后，肺癌A549细胞形态变得更加纤长，葡萄糖摄取率（P<0.05）及乳酸分泌率（P<0.01）明显增加,增殖与克隆形成能力明显增强（P<0.05）；此外，成熟脂肪细胞亦可促进A549细胞的迁移能力（P<0.05）、侵袭能力（P<0.01）以及胞内脂质的累积（P<0.05）。肿瘤微环境中脂肪细胞可通过影响肺腺癌A549细胞的糖脂代谢而促进其增值、迁移与侵袭。与此同时，课题组搜集不同类型、不同阶段肺癌患者血液标本和原发灶和骨转移灶标本，应用人脂肪细胞因子芯片对肺癌患者血液标本中脂肪细胞因子变化进行分析，期待寻找到促进肺癌骨转移的关键因子，以利于我们进一步认识肺癌骨转移机制，同时对开发新的防治肺癌骨转移药物，提高肺癌骨转移防治效果具有重要意义。