Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Ultrasound, Peking University People's Hospital, Beijing, China.
Prostate. 2022 May;82(6):695-705. doi: 10.1002/pros.24314. Epub 2022 Feb 15.
Prostate cancer (PCa) models in mice and rats are limited by their size and lack of a clearly delineated or easily accessible prostate gland. The canine PCa model is currently the only large animal model which can be used to test new preclinical interventions but is costly and availability is sparse. As an alternative, we developed an orthotopic human prostate tumor model in an immunosuppressed New Zealand White rabbit. Rabbits are phylogenetically closer to humans, their prostate gland is anatomically similar, and its size allows for clinically-relevant testing of interventions.
Rabbits were immunosuppressed via injection of cyclosporine. Human PC3pipGFP PCa cells were injected into the prostate via either (a) laparotomy or (b) transabdominal ultrasound (US) guided injection. Tumor growth was monitored using US and magnetic resonance imaging (MRI). Contrast-enhanced ultrasound (CEUS) imaging using nanobubbles and Lumason microbubbles was also performed to examine imaging features and determine the optimal contrast dose required for enhanced visualization of the tumor. Ex vivo fluorescence imaging, histopathology, and immunohistochemistry analyses of the collected tissues were performed to validate tumor morphology and prostate-specific membrane antigen (PSMA) expression.
Immunosuppression and tumor growth were, in general, well-tolerated by the rabbits. Fourteen out of 20 rabbits, with an average age of 8 months, successfully grew detectable tumors from Day 14 onwards after cell injection. The tumor growth rate was 39 ± 25 mm per week. CEUS and MRI of tumors appear hypoechoic and T2 hypointense, respectively, relative to normal prostate tissue. Minimally invasive US-guided tumor cell injection proved to be a better method compared to laparotomy due to the shorter recovery time required for the rabbits following injection. Among the rabbits that grew tumors, seven had tumors both inside and outside the prostate, three had tumors only inside the prostate, and four had tumors exclusively outside of the prostate. All tumors expressed the PSMA receptor.
We have established, for the first time, an orthotopic PCa rabbit model via percutaneous US-guided tumor cell inoculation. This animal model is an attractive, clinically relevant intermediate step to assess preclinical diagnostic and therapeutic compounds.
小鼠和大鼠的前列腺癌（PCa）模型受到其体型和前列腺缺乏明确界定或难以接近的限制。犬前列腺癌模型是目前唯一可用于测试新的临床前干预措施的大型动物模型，但成本高且供应稀少。作为替代方案，我们在免疫抑制的新西兰白兔中建立了原位人前列腺肿瘤模型。兔子在进化上与人类更接近，其前列腺在解剖上相似，其大小允许进行与临床相关的干预测试。
兔子通过注射环孢素进行免疫抑制。通过（a）剖腹术或（b）经腹超声（US）引导注射将人 PC3pipGFP PCa 细胞注入前列腺。使用 US 和磁共振成像（MRI）监测肿瘤生长。还进行了使用纳米气泡和 Lumason 微泡的对比增强超声（CEUS）成像，以检查成像特征并确定增强肿瘤可视化所需的最佳对比剂量。对收集的组织进行离体荧光成像、组织病理学和免疫组织化学分析，以验证肿瘤形态和前列腺特异性膜抗原（PSMA）表达。
免疫抑制和肿瘤生长总体上被兔子很好地耐受。20 只兔子中的 14 只，平均年龄为 8 个月，在细胞注射后 14 天开始成功生长可检测到的肿瘤。肿瘤生长速度为每周 39±25mm。与正常前列腺组织相比，肿瘤的 CEUS 和 MRI 分别呈低回声和 T2 低信号。与剖腹术相比，微创 US 引导的肿瘤细胞注射证明是一种更好的方法，因为注射后兔子需要的恢复时间更短。在生长肿瘤的兔子中，有 7 只兔子的肿瘤位于前列腺内和前列腺外，有 3 只兔子的肿瘤仅位于前列腺内，有 4 只兔子的肿瘤仅位于前列腺外。所有肿瘤均表达 PSMA 受体。
我们首次通过经皮 US 引导的肿瘤细胞接种建立了原位 PCa 兔模型。这种动物模型是评估临床前诊断和治疗化合物的有吸引力的临床相关中间步骤。
