Department of Molecular & Functional Imaging, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Clin Cancer Res. 2012 Jan 1;18(1):207-19. doi: 10.1158/1078-0432.CCR-11-0238. Epub 2011 Oct 20.
To develop targeted molecular imaging probes for the noninvasive detection of breast cancer lymph node metastasis.
Six cell surface or secreted markers were identified by expression profiling and from the literature as being highly expressed in breast cancer lymph node metastases. Two of these markers were cell surface carbonic anhydrase isozymes (CAIX and/or CAXII) and were validated for protein expression by immunohistochemistry of patient tissue samples on a breast cancer tissue microarray containing 47 normal breast tissue samples, 42 ductal carcinoma in situ, 43 invasive ductal carcinomas without metastasis, 46 invasive ductal carcinomas with metastasis, and 49 lymph node macrometastases of breast carcinoma. Targeted probes were developed by conjugation of CAIX- and CAXII-specific monoclonal antibodies to a near-infrared fluorescent dye.
Together, these two markers were expressed in 100% of the lymph node metastases surveyed. Selectivity of the imaging probes were confirmed by intravenous injection into nude mice-bearing mammary fat pad tumors of marker-expressing cells and nonexpressing cells or by preinjection of unlabeled antibody. Imaging of lymph node metastases showed that peritumorally injected probes detected nodes harboring metastatic tumor cells. As few as 1,000 cells were detected, as determined by implanting, under ultrasound guidance, a range in number of CAIX- and CAXII-expressing cells into the axillary lymph nodes.
These imaging probes have potential for noninvasive staging of breast cancer in the clinic and elimination of unneeded surgery, which is costly and associated with morbidities.
开发靶向分子成像探针，用于非侵入性检测乳腺癌淋巴结转移。
通过表达谱分析和文献综述，确定了 6 个细胞表面或分泌的标志物，这些标志物在乳腺癌淋巴结转移中高度表达。其中两个标志物是细胞表面碳酸酐酶同工酶（CAIX 和/或 CAXII），并通过对包含 47 例正常乳腺组织样本、42 例导管原位癌、43 例无转移浸润性导管癌、46 例有转移浸润性导管癌和 49 例乳腺癌淋巴结宏转移的乳腺癌组织微阵列上的患者组织样本进行免疫组织化学验证了其蛋白表达。靶向探针通过将 CAIX 和 CAXII 特异性单克隆抗体与近红外荧光染料缀合而开发。
这两个标志物在调查的所有淋巴结转移中均有表达，表达率为 100%。通过静脉注射表达标志物的细胞和不表达标志物的细胞，或通过预注射未标记的抗体，证实了成像探针的选择性。对淋巴结转移的成像显示，周围注射的探针可以检测到含有转移性肿瘤细胞的淋巴结。通过超声引导将一定数量的 CAIX 和 CAXII 表达细胞植入腋窝淋巴结，确定可以检测到低至 1000 个细胞。
这些成像探针具有在临床上进行非侵入性分期乳腺癌和消除不必要手术的潜力，手术不仅费用昂贵，而且还会引起各种并发症。
