Smith Myles J, Culhane Aedín C, Killeen Shane, Kelly Maura A, Wang Jiang H, Cotter Thomas G, Redmond Henry P
Department of Academic Surgery, Cork University Hospital, Cork, Ireland.
Ann Surg Oncol. 2008 Oct;15(10):2954-64. doi: 10.1245/s10434-008-0037-5. Epub 2008 Jul 12.
We aimed to identify mechanisms driving local recurrence in a model of breast-conserving surgery (BCS) for breast cancer.
Breast cancer recurrence after BCS remains a clinically significant, but poorly understood problem. We have previously reported that recurrent colorectal tumours demonstrate altered growth dynamics, increased metastatic burden and resistance to apoptosis, mediated by upregulation of phosphoinositide-3-kinase/Akt (PI3K/Akt). We investigated whether similar characteristics were evident in a model of locally recurrent breast cancer.
Tumours were generated by orthotopic inoculation of 4T1 cells in two groups of female Balb/c mice and cytoreductive surgery performed when mean tumour size was above 150 mm(3). Local recurrence was observed and gene expression was examined using Affymetrix GeneChips in primary and recurrent tumours. Differential expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Phosphorylation of Akt was assessed using Western immunoblotting. An ex vivo heat shock protein (HSP)-loaded dendritic cell vaccine was administered in the perioperative period.
We observed a significant difference in the recurrent 4T1 tumour volume and growth rate (p < 0.05). Gene expression studies suggested roles for the PI3K/Akt system and local immunosuppression driving the altered growth kinetics. We demonstrated that perioperative vaccination with an ex vivo HSP-loaded dendritic cell vaccine abrogated recurrent tumour growth in vivo (p = 0.003 at day 15).
Investigating therapies which target tumour survival pathways such as PI3K/Akt and boost immune surveillance in the perioperative period may be useful adjuncts to contemporary breast cancer treatment.
我们旨在确定乳腺癌保乳手术（BCS）模型中驱动局部复发的机制。
BCS术后乳腺癌复发仍是一个具有临床意义但了解甚少的问题。我们之前报道过，复发性结直肠肿瘤表现出改变的生长动力学、增加的转移负担以及对细胞凋亡的抗性，这些是由磷酸肌醇-3-激酶/蛋白激酶B（PI3K/Akt）上调介导的。我们研究了局部复发性乳腺癌模型中是否也有类似特征。
通过将4T1细胞原位接种到两组雌性Balb/c小鼠中生成肿瘤，当平均肿瘤大小超过150 mm³时进行减瘤手术。观察局部复发情况，并使用Affymetrix基因芯片检测原发性和复发性肿瘤中的基因表达。通过定量实时聚合酶链反应（qRT-PCR）确认差异表达。使用蛋白质免疫印迹法评估Akt的磷酸化。在围手术期给予体外热休克蛋白（HSP）负载的树突状细胞疫苗。
我们观察到复发性4T1肿瘤体积和生长速率存在显著差异（p < 0.05）。基因表达研究表明PI3K/Akt系统和局部免疫抑制在驱动改变的生长动力学中发挥作用。我们证明，围手术期给予体外HSP负载的树突状细胞疫苗可在体内消除复发性肿瘤生长（第15天时p = 0.003）。
研究针对PI3K/Akt等肿瘤生存途径并在围手术期增强免疫监视的疗法可能是当代乳腺癌治疗的有用辅助手段。
