癌细胞促生长激素神经肽作为乳腺癌转移性骨痛治疗靶点的实验研究

Metastatic cancer-induced bone pain (CIBP) is a pain of the most difficult to relieve, effective alleviation for CIBP is still world-class problem. The pain caused by bone metastasis of breast cancer is more common in clinical, Interestingly, the scientists found that more and more tumors can express Galanin (Gal), including breast cancer cells. Gal, a neuron peptide which is widespread in nerve system, is involved in nociception and the regulation of pain. A lot of studies demonstrated that complex mechanism of CIBP is involved in the direct invasion in primary afferent fibers by tumor and inflammatory stimuli and sensitization. But, It is unclear whether Gal of breast cancer cell is responsible for CIBP. Based on the background above, in the present study, the expression and regulation of Gal in breast cancer cell line and the regulation of pain related proteins in dorsal root ganglion (DRG) by Gal of breast cancer cell line will be observed. In the study, the Rat models of breast cancer cells-induced bone destruction will be established, moreover a variety of experimental methods will be used, the effects of Gal in breast cancer CIBP Rat models will be explored. We expected to provide rationale and experimental evidence for development and further studies of Gal on arising of breast cancer CIBP and therapeutic strategy for improving CIBP neuropathy.

转移性癌性骨痛（CIBP）是当今最难缓解的疼痛之一，CIBP的有效治疗目前仍是世界级的难题，其中乳腺癌骨转移引起的疼痛较常见。有趣的是近年来科学家发现越来越多肿瘤可表达促生长激素神经肽（Gal），包括乳腺癌细胞。Gal及其受体在神经系统广泛存在，它与伤害感受相关且参与痛觉的调节，大量研究证实Gal及其受体在多种类型神经病变和神经疼痛中发挥着重要的作用。但是乳腺癌细胞Gal在乳腺癌CIBP中发挥怎样的作用目前尚无文献报道。基于以上研究背景，本研究拟通过体外实验研究乳腺癌细胞Gal的表达及调控、乳腺癌细胞Gal对背根神经节疼痛相关蛋白的调控作用；通过建立乳腺癌CIBP大鼠模型，运用多种实验方法研究乳腺癌细胞Gal在乳腺癌转移性骨痛大鼠模型中的作用。本研究期望为乳腺癌CIBP的发病机制提供新的理论依据，评价Gal作为治疗新靶点的可行性。

乳腺癌转移性骨痛是一种复杂的慢性疼痛综合征，转移性癌性骨痛是当今最难缓解的疼痛之一，其有效治疗目前仍是世界级的难题。促生长激素神经肽（galanin, Gal）是一种典型的神经肽，目前已发现多种肿瘤表达Gal，包括乳腺癌细胞。Gal与伤害感受相关，参与痛觉的调节。我们的研究证实：①入选的9中常见乳腺癌细胞系中均表达Gal，其中HS578T细胞系Gal的表达量最低，细胞系ZR-75-1中 Gal的表达量最高。外源性破骨细胞相关因子TGF-β和PDGF可以促进乳腺癌细胞ZR-75-1中Gal的表达。②破骨细胞相关因子bFGF、TGF-β、PDGF、BMP和IGF可以促进DRG神经元中疼痛相关蛋白Gal、SP和CGRP的表达，说明它们在肿瘤骨转移性疼痛中发挥重要作用。另外本研究中TGF-β、bFGF和PDGF使DRG神经元中Gal及GalR系统表现出了一定的可塑性。③我们建立了Gal低表达乳腺癌转移性骨癌痛动物模型和Gal过表达乳腺癌转移性骨癌痛动物模型，证实乳腺癌细胞Gal可以减少DRG和脊髓神经元中的疼痛相关蛋白的表达，并且可以使大鼠痛觉敏感性下降，而此作用可能是通过GalR1发挥作用的。本研究为乳腺癌细胞Gal在乳腺癌转移性骨痛中的作用及机制提供了依据，为乳腺癌转移性骨痛的发病机制提供新的理论依据。