Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Clin Exp Metastasis. 2010 Apr;27(4):233-40. doi: 10.1007/s10585-010-9321-4. Epub 2010 Mar 13.
CXCL12/CXCR4 signaling, being important in the homing of cancer cells to lungs, bone and other organs, is a promising therapeutic target. Our purpose was to determine whether a peptide-based antagonist of CXCR4 would reduce primary tumor growth and/or metastasis in a preclinical mouse model of inflammatory breast cancer. We improved an existing model of inflammatory breast cancer for this study by luciferase transfection of SUM149 cells and the monitoring of such cells in mice by imaging and the luciferase assay. We implanted 2 x 10(6) SUM49-Luc cells along with matrigel into the left thoracic mammary fat pad of nude mice to produce tumors. Our mouse model exhibited important features of inflammatory breast cancer, namely, aggressive local disease, local metastases and distant metastases. To evaluate the efficacy of a CXCR4 antagonist CTCE-9908, by itself or in combination with paclitaxel, we treated groups of ten mice each with CTCE-9908 (25 mg/kg, injected subcutaneously 5 days/week), control peptide SC-9908, paclitaxel (10 mg/kg, injected subcutaneously twice a week), and CTCE-9908 plus paclitaxel concurrently. We assessed all mice weekly by whole-body luciferase imaging to quantify relative primary tumor burden and distant metastases. At the end of the experiment, we quantified primary tumors by weight and lung metastases by luciferase activity assay on tissue lysates. Paclitaxel, a known chemotherapeutic, inhibited primary tumor growth in our model (P < 0.05). CTCE-9908 did not significantly inhibit primary tumor growth or lung metastases as compared to control groups, without or with paclitaxel (P > 0.05). However, CTCE-9908 as a single therapy inhibited organ-specific metastasis to leg (P < 0.05 by chi-squared test and by two-sample t-test).
CXCL12/CXCR4 信号通路在癌细胞向肺部、骨骼和其他器官的归巢中起着重要作用，是一个有前途的治疗靶点。我们的目的是确定 CXCR4 的肽类拮抗剂是否会减少炎症性乳腺癌的临床前小鼠模型中的原发性肿瘤生长和/或转移。我们通过将荧光素酶转染 SUM149 细胞并通过成像和荧光素酶测定来监测这些细胞，改进了现有的炎症性乳腺癌模型。我们将 2 x 10(6) SUM49-Luc 细胞与基质胶一起植入裸鼠左胸乳腺脂肪垫中以产生肿瘤。我们的小鼠模型表现出炎症性乳腺癌的重要特征，即侵袭性局部疾病、局部转移和远处转移。为了评估 CXCR4 拮抗剂 CTCE-9908 的疗效，我们单独或与紫杉醇联合治疗每组 10 只小鼠，CTCE-9908（25 mg/kg，每周皮下注射 5 天），对照肽 SC-9908，紫杉醇（10 mg/kg，每周两次皮下注射）和 CTCE-9908 加紫杉醇同时。我们每周通过全身荧光素酶成像评估所有小鼠，以量化相对原发性肿瘤负担和远处转移。在实验结束时，我们通过组织裂解物上的荧光素酶活性测定来量化原发性肿瘤的重量和肺转移。紫杉醇，一种已知的化疗药物，抑制了我们模型中的原发性肿瘤生长（P <0.05）。与对照组相比，CTCE-9908 单独或与紫杉醇联合使用时，对原发性肿瘤生长或肺转移没有显著抑制作用（P > 0.05）。然而，CTCE-9908 作为单一疗法抑制了腿部的器官特异性转移（通过卡方检验和两样本 t 检验，P <0.05）。
