肿瘤相关骨髓基质中HA代谢异常在调控乳腺癌干细胞由休眠到激活状态转变过程中的作用及机制研究

Bone is the most common organ affected by distant relapse of breast cancer. However, the mechanisms involved are unknown. Recent evidence suggests that the metastasis-initiating cells are cancer stem cells (CSCs), which may remain dormant in bone marrow niche and enter reactivation under specialized extracellular matrix (ECM) niches. The ECM niches may be remodeled by the metabolic abnormalities of hyaluronan (HA), which is the main component of the ECM. CD44, the major cell surface receptor of HA, is commonly used as cell-surface marker for breast CSCs. Increasing evidence showed that the HA-CD44 interaction was closely related to the dormant state of breast cancer cells and mediated the metastasis to bone, though the mechanisms involved are still unclear. Previous work from our laboratory showed that ①The serum HA levels were determined. After analyzed 176 clinical serum specimens from breast cancer and benign breast disease, we found that the increased concentration of HA and its degradation fragment-oHA in breast cancer are associated with lymph node metastasis. ②HA is over-expressed in cancer-associated bone marrow. For the first time, this project tries to understand the metabolic abnormalities of HA in the cancer-associated bone marrow and its effects on the dormant-to-proliferative switch of cancer stem cells, including two parts: ①To observe the metabolic abnormalities of HA in the cancer-associated bone marrow. ② To study the role of the abnormal HA in triggering the dormant-to-proliferative switch of cancer stem cells and the mechanisms involved. The project may provide a new insight to elucidate the mechanism of bone metastasis in breast cancer.

乳腺癌易发骨转移，肿瘤干细胞（CSC）可能是转移元凶，是近年热点。据报道骨转移形成前CSC是休眠状态，但易受微环境影响转入再激活。骨微环境是CSC生存土壤，其中细胞外基质（ECM）常被重构。透明质酸HA是ECM主要成分，据报道乳腺癌原位组织中HA代谢异常导致的ECM重塑与肿瘤转移度正相关。本课题前期①乳癌患者血清HA代谢异常且与转移度正相关②肿瘤相关骨基质中HA异常增加，提示其代谢异常。据报HA与受体CD44参与乳腺癌细胞增殖、分化和侵袭，并与休眠及骨转移有关。新近发现CD44除为乳腺CSC表面标志分子，还与其干性维持有关。推测骨髓HA代谢异常可能通过CD44参与调控CSC的休眠与再激活状态。本项目拟首次聚焦乳腺癌相关骨髓HA代谢及其对CSC向再激活转变的调控。内容①明确乳癌相关骨髓HA代谢是否异常②探讨骨基质中异常HA在CSC从休眠向再激活转变中的作用及机制。力从新视角阐明乳癌骨转移机制

乳腺癌易发骨转移，转移的乳腺癌细胞在骨内的生存状态主要有两种：以细胞周期停滞在G0/G1期为主要特征的“休眠”或以细胞分裂的方式产生新的细胞为主要特征的“增殖”。两种乳腺癌肿瘤细胞的生长状态，主要取决于骨髓微环境。但是骨髓微环境支持转移性乳腺癌细胞在骨髓内增殖或休眠的机制尚不清楚。所以，进一步探明骨髓微环境对乳腺癌细胞的影响迫在眉睫。骨微环境细胞外基质（ECM）常被重构。透明质酸（HA）是ECM主要成分。据报道乳腺癌原位组织中HA代谢异常导致的ECM重塑与肿瘤转移度正相关。本课题前期①乳癌患者血清HA代谢异常且与转移度正相关②肿瘤相关骨基质中HA异常增加，提示其代谢异常。据报HA与受体CD44参与乳腺癌细胞增殖、分化和侵袭，并与休眠及骨转移有关。推测骨髓HA代谢异常可能通过CD44参与调控乳腺癌细胞的休眠与再激活状态。本项目拟首次聚焦乳腺癌相关骨髓HA代谢改变及其对进入骨髓微环境的乳腺癌细胞由静止向再激活转变的调控，力从新视角阐明乳癌骨转移机制。.研究内容包括：①明确肿瘤相关骨髓基质中透明质酸（hyaluronan）代谢的改变；②探明天然高分子量透明质酸（HMW-HA）抑制亲骨性肿瘤细胞增殖、进而诱导其进入休眠状态的作用及机理；③肿瘤相关骨髓微环境HA代谢异常变化及对乳腺癌细胞生长的调控。.本课题证实①HMW-HA调控乳腺癌细胞的细胞周期，介导乳腺癌细胞生长抑制；②肿瘤相关骨髓基质细胞微环境HA代谢异常增多，HA为混合分子量HA，主要来自骨髓基质细胞HS-5，异常代谢的HA能够促进乳腺癌细胞生长。.本课题的研究探讨了骨髓微环境来源的HA的动态变化对乳腺癌细胞的不同影响，为理解肿瘤细胞与微环境的相互作用提供充实的依据，为寻找骨转移治疗提供新的理论和靶点。