Frame Gavin, Huang Xiaoyong, Haas Roni, Khan Kabir A, Leong Hon S, Kislinger Thomas, Boutros Paul C, Downes Michelle, Liu Stanley K
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
Sci Rep. 2024 Dec 28;14(1):31205. doi: 10.1038/s41598-024-82546-w.
Globally, prostate cancer is the second most common malignancy in males, with over 400 thousand men dying from the disease each year. A common treatment modality for localized prostate cancer is radiotherapy. However, up to half of high-risk patients can relapse with radiorecurrent prostate cancer, the aggressive clinical progression of which remains severely understudied. To address this, we have established an orthotopic mouse model for study that recapitulates the aggressive clinical progression of radiorecurrent prostate cancer. Radiorecurrent DU145 cells which survived conventional fraction (CF) irradiation were orthotopically injected into the prostates of athymic nude mice and monitored with bioluminescent imaging. CF tumours exhibited higher take rates and grew more rapidly than treatment-naïve parental tumours (PAR). Pathohistological analysis revealed extensive seminal vesicle invasion and necrosis in CF tumours, recapitulating the aggressive progression towards locally advanced disease exhibited by radiorecurrent tumours clinically. RNA sequencing of CF and PAR tumours identified ROBO1, CAV1, and CDH1 as candidate targets of radiorecurrent progression associated with biochemical relapse clinically. Together, this study presents a clinically relevant orthotopic model of radiorecurrent prostate cancer progression that will enable discovery of targets for therapeutic intervention to improve outcomes in prostate cancer patients.
在全球范围内，前列腺癌是男性中第二常见的恶性肿瘤，每年有超过40万男性死于该疾病。局部前列腺癌的一种常见治疗方式是放射治疗。然而，高达一半的高危患者会复发为放射性复发性前列腺癌，其侵袭性临床进展仍严重缺乏研究。为了解决这个问题，我们建立了一种用于研究的原位小鼠模型，该模型概括了放射性复发性前列腺癌的侵袭性临床进展。将在常规分割（CF）照射后存活的放射性复发性DU145细胞原位注射到无胸腺裸鼠的前列腺中，并通过生物发光成像进行监测。与未接受过治疗的亲代肿瘤（PAR）相比，CF肿瘤表现出更高的接种率且生长更快。病理组织学分析显示CF肿瘤中存在广泛的精囊侵犯和坏死，重现了放射性复发性肿瘤临床上向局部晚期疾病的侵袭性进展。对CF和PAR肿瘤进行RNA测序，确定ROBO1、CAV1和CDH1是与临床上生化复发相关的放射性复发性进展的候选靶点。总之，本研究提出了一种与临床相关的放射性复发性前列腺癌进展原位模型，这将有助于发现治疗干预靶点，以改善前列腺癌患者的治疗结果。
