分泌型海肾荧光素酶作为一种生物标志物，用于监测系统性转移的肿瘤进展和治疗反应。
Secreted Gaussia luciferase as a biomarker for monitoring tumor progression and treatment response of systemic metastases.
机构信息
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
出版信息
PLoS One. 2009 Dec 15;4(12):e8316. doi: 10.1371/journal.pone.0008316.
BACKGROUND
Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc), and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses.
METHODOLOGY/PRINCIPAL FINDINGS: We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI). Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R(2) = 0.84) and urine (R(2) = 0.55) in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2.
CONCLUSION/SIGNIFICANCE: We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.
背景
目前，只有少数技术可用于量化临床前模型中的系统性转移。因此，迫切需要能够灵敏地检测转移性定植并实时评估治疗反应的技术。为此，我们设计了表达天然分泌型海肾荧光素酶（Gluc）的肿瘤细胞，并研究了其作为监测活转移性或原发性肿瘤生长及其治疗反应的循环生物标志物的用途。
方法/主要发现：我们首先利用 MDA-MB-231 细胞系的衍生细胞建立了表达 Gluc 的原位原发性和转移性乳腺癌肿瘤。然后，我们将肿瘤负荷与血液和尿液中的 Gluc 活性以及生物发光成像（BLI）进行了关联。其次，我们利用血液 Gluc 检测法来监测实验性系统性转移模型中拉帕替尼的治疗反应。我们观察到在乳腺癌模型中，原发性肿瘤体积与血液（R(2) = 0.84）和尿液（R(2) = 0.55）中的 Gluc 浓度之间存在良好的相关性。随着原发性肿瘤的生长，由于活肿瘤分数的减少，相关性发生了偏离。我们的肿瘤生长数学模型也支持了这一点，该模型用于比较我们模型中的总肿瘤和活肿瘤负担。在实验性转移模型中，我们发现了许多脑转移以及包括骨和肺在内的系统性转移。重要的是，血液 Gluc 检测法在 BLI 能够观察到其存在之前就揭示了转移性肿瘤的早期生长。利用分泌型 Gluc，我们通过 BLI 定位了系统性转移，并通过血液 Gluc 检测法在 lapatinib（一种 EGFR 和 HER2 的双重酪氨酸激酶抑制剂）治疗过程中定量监测了总活转移性肿瘤负担，从而对其进行了监测。
结论/意义：我们证明了分泌型 Gluc 检测法准确反映了原发性和转移性肿瘤中活癌细胞的数量。血液 Gluc 活性不仅可以跟踪转移性肿瘤的进展，还可以作为肿瘤对治疗反应的纵向生物标志物。
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