肿瘤微环境LMW-HA/HMW-HA失衡在调控淋巴管新生中的作用及机制研究

Lymphangiogenesis is reported to be actively involved in lymphatic metastasis. The molecular mechanism of lymphangiogenesis is, however, poorly understood. Tumor microenvironment plays a key role in metastasis. Hyaluronan (HA), one of the main components of the extracellular matrix (ECM), is critical for cancer progress. Biological responses triggered by HA depend on the HA polymer length. Lots of studies proved that HA fragments or low molecular weight HA (LMW-HA) exhibit pro-angiogenesis effects, whereas native high molecular weight HA (HMW-HA) inhibit angiogenesis. Until now, little is known about HA on its role in regulating lymphangiogenesis. Previous study from our laboratory showed that: (1)Elevated serum levels of LMW-HA but not total HA correlate with breast cancer lymphatic metastasis; (2)Compared to the normal cells, increased levels of LMW-HA were found in highly invasive breast cancer cells; (3)Exogenous LMW-HA but not native HMW-HA significantly increased lymphatic endothelial cells (LECs) proliferation, migration and tube formation. All results suggested that the balance between LMW-HA and HMW-HA in tumor microenvironment might be disrupted, which might in turn contribute to the cancer progress through regulation of lymphangiogenesis. For the first time, our study aim to investigate the role of tumor-associated disruption of LMW-HA/HMW-HA balance in lymphangiogenesis and explore its underlying mechanism. Contents:(1)Clarify the change of LMW-HA/HMW-HA balance in the human colon tumor matrix，verify the exact molecular weight distribution of HA in tumor microenvironment and understand its association with lymphangiogenesis and lymph metastasis; (2)Mechanism study on the direct and indirect role of tumor associated disruption of LMW-HA/HMW-HA balance in lymphangiogenesis.

肿瘤淋巴管新生与肿瘤淋巴转移密切相关，具体机制不明。肿瘤微环境是决定肿瘤转移的关键因素。透明质酸(HA)是细胞外基质的主要成分，对肿瘤发生发展有着重要影响。已证实HA降解片段(LMW-HA)促进血管新生，原始HA巨分子(HMW-HA)则发挥抑制作用。然而HA与淋巴管新生的关系尚缺乏研究。本课题前期研究提示(1)血清LMW-HA水平与肿瘤淋巴转移正相关;(2)高转移肿瘤细胞较正常细胞LMW-HA合成显著增加;(3)外源性LMW-HA促进淋巴管新生，而HMW-HA无此作用。提示肿瘤微环境LMW-HA/HMW-HA失衡可能参与调控淋巴管新生，促进肿瘤淋巴转移。本课题首次探究肿瘤微环境LMW-HA/HMW-HA失衡在调控淋巴管新生中的作用及机制。内容(1)探明人结肠癌微环境LMW-HA/HMW-HA失衡与肿瘤淋巴管新生的相关性(2)探究LMW-HA/HMW-HA失衡在淋巴管新生中的作用及分子机制。

肿瘤淋巴管新生与肿瘤淋巴转移密切相关，具体机制不明。肿瘤微环境是决定肿瘤转移的关键因素。透明质酸(HA)是细胞外基质的主要成分，对肿瘤发生发展有着重要影响。已证实HA降解片段(LMW-HA)促进血管新生，原始HA巨分子(HMW-HA)则发挥抑制作用。然而HA与淋巴管新生的关系尚缺乏研究。本课题以结直肠肿瘤为例，试图阐明肿瘤转移相关的LMW-HA/HMW-HA 平衡的改变，并进一步探究其在调控肿瘤淋巴管新生中的作用及机制。具体研究内容为：（1）分析人结直肠癌组织间质中HA 的分子量及含量，明确肿瘤微环境中的LMW-HA/HMW-HA失衡，探讨其与肿瘤淋巴管新生的相关性；（2）分离肿瘤患者组织和血清中肿瘤相关LMW-HA，结合患者临床信息探索其临床价值；（3）探究微环境中LMW-HA/HMW-HA 失衡在调控肿瘤淋巴管新生中的直接和间接作用及分子机制。所取得的重要结果：（1）证实肿瘤微环境中存在LMW-HA/HMW-HA失衡状态，LMW-HA含量显著增高，分子量集中在30kDa以下，约为6kDa；（2）肿瘤患者组织和血清中肿瘤相关LMW-HA水平与淋巴转移呈正相关，血清肿瘤相关LMW-HA具有作为结直肠癌肿瘤标志物的潜能；（3）体外证实LMW-HA可诱导淋巴管新生,并初步探索了其分子机制。本研究发现肿瘤相关LMW-HA具有辅助诊断结直肠肿瘤的价值，同时具有预测肿瘤复发的潜能，具有重要的临床意义。结合临床结果，本研究探索了肿瘤相关LMW-HA促进淋巴转移的机制，发现其可促进淋巴管新生，并初步探索了分子机制，为阐明结直肠肿瘤淋巴转移提供了新的理论基础。