基于超声弹性成像及分子影像技术的浸润性乳腺癌实时病理诊断

Invasive cancer is the most common type of breast cancer, the current diagnosis depends either on tissue biopsy or surgical pathology, which are invasive diagnosis. Shear wave elastography has been put forward in recent 5 years, which is added to the conventional color Doppler ultrasound equipment to quantitatively judge the hardness of tissues, and it can also be used as a powerful means for the diagnosis of the invasive breast cancer. In 2017, we have firstly mentioned that the hardness of the invasive ductal carcinoma has relation with collagen fiber morphology and its arrangement, which is the main component of the extra cellular matrix(ECM). Therefore, we intend to find important target molecules affecting the hardness of the invasive breast cancer in the fibrosis signaling pathway through clinical basic research, and then fabricate the targeted probes. To verify the target property of the probes through animal experiments. Then we sprinkle the targeted probe to the lesions which were cut off in the surgery, and use imaging technique to observe the feasibility and accuracy of the real-time pathology during operation. Through cooperation with Chinese Academy of Sciences Institute of Biophysics, we want to acquire the molecular biology basis of the hardness, these studies may help us to understand the molecular mechanism of hardness, and provide a new method for the treatment of breast cancer, which will have theoretical significance. Besides, if the noninvasive real-time pathology is feasible, it will promote the traditional pathology and explore the possibility of its transformation to clinic.

浸润性癌是乳腺癌中最常见的类型，目前确诊依赖组织活检或手术病理，属有创性病理诊断。近5年推出剪切波弹性成像，该技术加在常规彩超设备内，对组织的硬度进行定量判断，可作为浸润性乳腺癌有力的辅助手段。2017年，我们在国内外首先提出：最常见的浸润性导管癌的硬度与细胞外基质中胶原纤维形态和排列方式有关。所以，我们拟先通过临床基础研究，寻找影响浸润性癌硬度的纤维信号通路中关键靶分子,制作靶向探针；再通过相关动物实验验证探针的靶向性；随后将靶向探针喷洒到手术切下来的病灶处，采用分子影像技术观察术中实时病理的可行性和精确性。通过与中科院生物物理研究所联合研究，一方面获得浸润性癌硬度变化的分子生物学基础，了解形成硬度的分子机制，同时有望为乳腺癌治疗提供另一思路，具有理论意义；另一方面，无创实时病理如果可行，将推动传统有创病理向前一步。

浸润性癌是乳腺癌中最常见的类型，目前确诊依赖组织活检或手术病理，属有创性病理诊断。剪切波弹性成像（SWE）是近几年来新的检查技术，可以快速、实时的获得组织硬度信息。本课题组前期研究表明乳腺癌硬度与细胞外基质胶原纤维形态及排列方式有关。本研究拟通过临床基础研究，寻找影响浸润性乳腺癌硬度的纤维信号通路中关键靶分子，制作靶向探针；随后将靶向探针喷洒到手术切下来的病灶处，采用分子影像技术观察术中实时病理的可行性和精确性。通过研究发现浸润性乳腺癌中整合素相互作用蛋白Kindlin-2表达水平与SWE中最大弹性模量值（Emax）及胶原纤维含量正相关。Kindlin-2通过TGFβ/Smad信号通路和Integrin信号通路影响浸润性乳腺癌硬度及淋巴结转移。我们还发现癌症内低氧微环境诱导HIF-1α分子表达，HIF-1α通过mTOR/HIF-1α/P4HA1和EMT信号通路影响浸润性乳腺癌硬度及患者预后。进一步研究发现HIF-1α和Kindlin-2相互作用共同影响浸润性乳腺癌的硬度。通过一系列研究，我们首次发现并报道浸润性乳腺癌硬度的微观病理分子机制，为浸润性乳腺癌精准靶向病理诊断及判断预后提供依据。