Tai Lee-Hwa, Tanese de Souza Christiano, Sahi Shalini, Zhang Jiqing, Alkayyal Almohanad A, Ananth Abhirami Anu, Auer Rebecca A C
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute.
Centre for Innovative Cancer Research, Ottawa Hospital Research Institute; Department of Cellular and Molecular Medicine, University of Ottawa; Department of Neurosurgery, The Second Hospital of Shandong University.
J Vis Exp. 2014 Mar 12(85):51253. doi: 10.3791/51253.
Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.
手术切除是大多数癌症患者的重要治疗方法，但手术会导致免疫系统功能障碍，这在动物模型和癌症患者中都与转移性疾病的发展有关。我们团队和其他团队的临床前研究表明，术后先天性免疫功能会受到显著抑制，特别是自然杀伤细胞（NK细胞），这在术后转移灶的加速发展中起主要作用。相对较少的动物研究和临床试验专注于表征和逆转癌症手术的有害影响。使用自发转移肿瘤和手术应激的严格动物模型，证明了癌症手术对肺转移发展的促进作用。在这个模型中，将4T1乳腺癌细胞植入小鼠乳腺脂肪垫。在肿瘤植入后第14天，对所有动物的原发性乳腺肿瘤进行完整切除。一部分动物接受腹部肾切除术形式的额外手术应激。在第28天，对肺肿瘤结节进行定量。当在术前立即给予免疫治疗时，检测到免疫细胞的显著激活，这阻止了术后转移的发生。虽然4T1乳腺肿瘤手术模型可以模拟腹部手术应激对肿瘤转移的影响，但其对其他肿瘤类型的适用性需要进行测试。当前的挑战是在临床前小鼠模型中识别安全且有前景的免疫疗法，并将其转化为可行的围手术期疗法，用于癌症手术患者以预防转移性疾病的复发。
