Department of Hepatology & Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
ECRC Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
J Exp Clin Cancer Res. 2024 May 30;43(1):153. doi: 10.1186/s13046-024-03066-z.
Surgery represents the only curative treatment option for pancreatic ductal adenocarcinoma (PDAC), but recurrence in more than 85% of patients limits the success of curative-intent tumor resection. Neural invasion (NI), particularly the spread of tumor cells along nerves into extratumoral regions of the pancreas, constitutes a well-recognized risk factor for recurrence. Hence, monitoring and therapeutic targeting of NI offer the potential to stratify recurrence risk and improve recurrence-free survival. Based on the evolutionary conserved dual function of axon and vessel guidance molecules, we hypothesize that the proangiogenic vessel guidance factor placental growth factor (PlGF) fosters NI. To test this hypothesis, we correlated PlGF with NI in PDAC patient samples and functionally assessed its role for the interaction of tumor cells with nerves.
Serum levels of PlGF and its soluble receptor sFlt1, and expression of PlGF mRNA transcripts in tumor tissues were determined by ELISA or qPCR in a retrospective discovery and a prospective validation cohort. Free circulating PlGF was calculated from the ratio PlGF/sFlt1. Incidence and extent of NI were quantified based on histomorphometric measurements and separately assessed for intratumoral and extratumoral nerves. PlGF function on reciprocal chemoattraction and directed neurite outgrowth was evaluated in co-cultures of PDAC cells with primary dorsal-root-ganglia neurons or Schwann cells using blocking anti-PlGF antibodies.
Elevated circulating levels of free PlGF correlated with NI and shorter overall survival in patients with PDAC qualifying for curative-intent surgery. Furthermore, high tissue PlGF mRNA transcript levels in patients undergoing curative-intent surgery correlated with a higher incidence and greater extent of NI spreading to tumor-distant extratumoral nerves. In turn, more abundant extratumoral NI predicted shorter disease-free and overall survival. Experimentally, PlGF facilitated directional and dynamic changes in neurite outgrowth of primary dorsal-root-ganglia neurons upon exposure to PDAC derived guidance and growth factors and supported mutual chemoattraction of tumor cells with neurons and Schwann cells.
Our translational results highlight PlGF as an axon guidance factor, which fosters neurite outgrowth and attracts tumor cells towards nerves. Hence, PlGF represents a promising circulating biomarker of NI and potential therapeutic target to improve the clinical outcome for patients with resectable PDAC.
手术是治疗胰腺导管腺癌（PDAC）的唯一根治性治疗选择，但超过 85%的患者复发限制了根治性肿瘤切除的成功。神经侵袭（NI），特别是肿瘤细胞沿着神经扩散到胰腺外肿瘤区域，是复发的一个公认的危险因素。因此，监测和治疗 NI 为分层复发风险和提高无复发生存率提供了可能。基于轴突和血管导向分子的进化保守双重功能，我们假设促血管生成的血管导向因子胎盘生长因子（PlGF）促进 NI。为了验证这一假设，我们在 PDAC 患者样本中对 PlGF 与 NI 进行了相关性分析，并在功能上评估了其对肿瘤细胞与神经相互作用的作用。
通过 ELISA 或 qPCR 检测回顾性发现队列和前瞻性验证队列中 PDAC 患者血清 PlGF 及其可溶性受体 sFlt1 的水平，以及肿瘤组织中 PlGF mRNA 转录本的表达。通过 PlGF/sFlt1 的比值计算游离循环 PlGF。根据组织形态学测量量化 NI 的发生率和程度，并分别评估肿瘤内和肿瘤外神经。使用阻断抗 PlGF 抗体，在 PDAC 细胞与原代背根神经节神经元或施万细胞的共培养物中评估 PlGF 对互惠趋化性和定向神经突生长的作用。
可用于根治性手术的 PDAC 患者中，循环中游离 PlGF 水平升高与 NI 相关，并与总生存期缩短相关。此外，接受根治性手术的患者组织中 PlGF mRNA 转录本水平较高，与向肿瘤远处肿瘤外神经扩散的 NI 发生率和程度较高相关。反过来，更多的肿瘤外 NI 预测无病生存期和总生存期较短。实验上，PlGF 促进了原代背根神经节神经元的定向和动态神经突生长变化，当暴露于 PDAC 衍生的导向和生长因子时，并支持肿瘤细胞与神经元和施万细胞的相互趋化作用。
我们的转化研究结果强调 PlGF 作为一种轴突导向因子，促进神经突生长并吸引肿瘤细胞向神经移动。因此，PlGF 代表了一种有前途的 NI 循环生物标志物，有望成为改善可切除 PDAC 患者临床结局的潜在治疗靶点。
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