Department of Pharmacology and Cancer Biology, Duke University, Durham, United States.
Elife. 2019 Apr 16;8:e43653. doi: 10.7554/eLife.43653.
Over half of breast-cancer-related deaths are due to recurrence 5 or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.
超过一半的乳腺癌相关死亡是由于初始诊断和治疗后 5 年或更长时间的复发。这种潜伏期表明，存在一部分残留的肿瘤细胞可以在治疗后存活下来，并在休眠状态下持续多年。微环境在治疗后调节残留细胞的存活和增殖中的作用仍未得到探索。我们使用 Her2 驱动的乳腺癌的条件性小鼠模型，确定了残留肿瘤细胞与其微环境之间的相互作用对于促进肿瘤复发至关重要。Her2 下调导致 TNFα/NFκB 信号驱动的炎症程序，促进了消退和残留肿瘤中免疫细胞的浸润。CCL5 细胞因子在 Her2 下调后升高，并在残留肿瘤中保持高水平。CCL5 通过募集表达 CCR5 的巨噬细胞促进肿瘤复发，这可能有助于残留肿瘤中胶原的沉积。阻断这个 TNFα-CCL5-巨噬细胞轴可能对预防乳腺癌复发有效。
