Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.
J Nucl Med. 2013 Nov;54(11):1883-9. doi: 10.2967/jnumed.112.117796. Epub 2013 Sep 12.
The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy.
Peritoneal or omental biopsies obtained from women diagnosed with stage I, stage II, or stage III/IV ovarian cancer were evaluated by immunohistochemistry. The effects of carboplatin on mesothelial VCAM-1 expression were determined in cultured cells by Western blot. Radiolabeled VCAM-1-specific peptide imaging probes and SPECT were used in a mouse model of ovarian cancer peritoneal metastasis to identify VCAM-1 as a viable imaging target.
VCAM-1 expression correlated with tumor stage. All specimens from stage I patients were negative, whereas 29% of stage II patients and 73% of stage III/IV patients were positive. Although most women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. Treatment of mesothelial cells in culture with carboplatin resulted in a transient decrease in VCAM-1 expression 4 h after treatment that returned to baseline within 16-24 h. In vivo imaging of VCAM-1 also demonstrated an acute decrease in expression 4 h after carboplatin administration that recovered within 48 h in mice harboring platinum-resistant tumors. Chronic VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden after treatment.
Clinically relevant VCAM-1-specific imaging probes identify VCAM-1 expression as an indicator of ovarian cancer peritoneal metastasis and therapeutic response to platinum-based agents. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease.
未能成功治疗卵巢癌患者在很大程度上是由于疾病在诊断时已处于晚期、对铂类药物产生耐药性以及缺乏监测肿瘤进展和治疗反应的敏感方法。血管细胞黏附分子-1（VCAM-1）在卵巢癌患者的间皮细胞上表达。我们研究了 VCAM-1 表达作为腹膜转移和对基于铂类药物的化疗反应的标志物。
通过免疫组织化学评估来自诊断为 I 期、II 期或 III/IV 期卵巢癌的女性的腹膜或网膜活检。通过 Western blot 确定顺铂对培养细胞中间皮 VCAM-1 表达的影响。放射性标记的 VCAM-1 特异性肽成像探针和 SPECT 用于卵巢癌腹膜转移的小鼠模型，以确定 VCAM-1 作为可行的成像靶标。
VCAM-1 表达与肿瘤分期相关。所有 I 期患者的标本均为阴性，而 29%的 II 期患者和 73%的 III/IV 期患者为阳性。尽管大多数患有晚期疾病的女性表达 VCAM-1，但接受新辅助化疗的女性中表达的发生率降低，表明化疗在调节 VCAM-1 表达方面发挥作用。用顺铂处理培养中的间皮细胞，在治疗后 4 小时 VCAM-1 表达短暂下降，在 16-24 小时内恢复基线水平。体内 VCAM-1 成像也表明，在顺铂给药后 4 小时 VCAM-1 表达急性下降，在携带铂类耐药肿瘤的小鼠中，在 48 小时内恢复。慢性 VCAM-1 表达反映了铂类药物治疗对肿瘤负担的影响。具体来说，顺铂治疗铂类敏感肿瘤的小鼠显示 VCAM-1 表达减少，与肿瘤负担减少相关；铂类耐药肿瘤的小鼠在治疗后仍保持 VCAM-1 表达和肿瘤负担升高。
临床相关的 VCAM-1 特异性成像探针将 VCAM-1 表达鉴定为卵巢癌腹膜转移和对铂类药物治疗反应的标志物。这些观察结果支持测试 VCAM-1 成像探针在监测卵巢癌患者治疗反应中的效用，从而有可能改善该疾病患者的管理。
