Abstract:
Colorectal cancer (CRC) is the third most common cancer worldwide. In the United States alone, CRC was responsible for approximately 52,550 deaths in 2023, with an estimated 153,020 new cases. CRC presents with synchronous peritoneal spread in 5-10% of patients, and up to 20-50% of patients with recurrent disease will develop metachronous colorectal cancer peritoneal metastatic (CRC-PM) disease. Eradication of the tumor, tumor margins and microscopic residual disease is paramount, as microscopic residual disease is associated with local recurrences, with 5-year survival rates of less than 35%. The success of resection and reduction of residual disease depends on the accuracy with which cancer cells and normal tissue can be intra-operatively distinguished. Fluorescence Molecular Imaging (IFMI) and tumor-targeted contrast agents represent a promising approach for intraoperative detection and surgical intervention. Proper target selection, the development of scalable imaging agents and enhanced real-time tumor and tumor microenvironment imaging are critical to enabling enhanced surgical resection. LGR5 (leucine-rich repeat-containing G-protein-coupled receptor 5), a colonic crypt stem cell marker and the receptor for the R-spondins (RSPO) in the Wnt signaling pathway, is also expressed on colorectal cancer stem cells (CSC) and on CRC tumors and metastases, suggesting it could be a useful target for imaging of CRC. However, there are numerous diverging reports on the role of LGR5 in CRC therapy and outcomes. Herein, we report on the synthesis and validation of a 37 amino acid RSPO1-mimetic peptide, termed RC18, that was specifically designed to access the R-spondin binding site of LGR5 to potentially be used for interoperative imaging of CRC-PM. The receptor-binding capabilities of the RC18 indicate that direct interactions with LGR5 neither significantly increased LGR5 signaling nor blocked RSPO1 binding and signal transduction, suggesting that the RSPO1-mimetic is functionally inert, making it an attractive contrast agent for intraoperative CRC-PM imaging.
摘要:
结直肠癌(CRC)是全球第三大最常见的癌症。仅在美国,CRC在2023年造成约52,550例死亡,估计有153,020例新病例。CRC在5-10%的患者中表现为同步腹膜扩散,多达20-50%的复发性疾病患者将发展为异时性结直肠癌腹膜转移(CRC-PM)疾病。肿瘤的根除,肿瘤边缘和微观残留疾病是最重要的,由于微观残留疾病与局部复发有关,5年生存率低于35%。切除和减少残留疾病的成功取决于术中区分癌细胞和正常组织的准确性。荧光分子成像(IFMI)和肿瘤靶向造影剂代表了一种有希望的术中检测和手术干预方法。正确的目标选择,可扩展显像剂的开发和增强的实时肿瘤和肿瘤微环境成像对于实现增强的手术切除至关重要.LGR5(富含亮氨酸重复序列的G蛋白偶联受体5),结肠隐窝干细胞标记物和Wnt信号通路中R-spondins(RSPO)的受体,在结直肠癌干细胞(CSC)和CRC肿瘤和转移瘤上也表达,提示它可能是CRC成像的有用目标。然而,关于LGR5在CRC治疗和结局中的作用,有许多不同的报道.在这里,我们报道了37个氨基酸的RSPO1模拟肽的合成和验证,称为RC18,专门设计用于访问LGR5的R-spondin结合位点,从而可能用于CRC-PM的手术间成像。RC18的受体结合能力表明与LGR5的直接相互作用既不显著增加LGR5信号传导,也不阻断RSPO1结合和信号转导,这表明RSPO1模拟物在功能上是惰性的,使其成为术中CRC-PM成像的有吸引力的造影剂。