Robinson Amy, Burgess Matthew, Webb Sheila, Louwe Pieter A, Ouyang Zhengyu, Skola Dylan, Han Claudia Z, Batada Nizar N, González-Huici Víctor, Cassetta Luca, Glass Chris K, Jenkins Stephen J, Pollard Jeffery W
MRC-Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Cancers (Basel). 2022 Feb 7;14(3):833. doi: 10.3390/cancers14030833.
There is a growing body of evidence that cancer causes systemic changes. These influences are most evident in the bone marrow and the blood, particularly in the myeloid compartment. Here, we show that there is an increase in the number of bone marrow, circulating and splenic monocytes by using mouse models of breast cancer caused by the mammary epithelial expression of the polyoma middle T antigen. Cancer does not affect ratios of classical to non-classical populations of monocytes in the circulation nor does it affect their half-lives. Single cell RNA sequencing also indicates that cancer does not induce any new monocyte populations. Cancer does not change the monocytic progenitor number in the bone marrow, but the proliferation rate of monocytes is higher, thus providing an explanation for the expansion of the circulating numbers. Deep RNA sequencing of these monocytic populations reveals that cancer causes changes in the classical monocyte compartment, with changes evident in bone marrow monocytes and even more so in the blood, suggesting influences in both compartments, with the down-regulation of interferon type 1 signaling and antigen presentation being the most prominent of these. Consistent with this analysis, down-regulated genes are enriched with STAT1/STAT2 binding sites in their promoter, which are transcription factors required for type 1 interferon signaling. However, these transcriptome changes in mice did not replicate those found in patients with breast cancer. Consequently, this mouse model of breast cancer may be insufficient to study the systemic influences of human cancer.
越来越多的证据表明癌症会引发全身变化。这些影响在骨髓和血液中最为明显，尤其是在髓系细胞区室。在此，我们利用多瘤病毒中T抗原在乳腺上皮表达所引发的乳腺癌小鼠模型，表明骨髓、循环血液和脾脏中的单核细胞数量有所增加。癌症并不影响循环血液中经典单核细胞与非经典单核细胞群体的比例，也不影响它们的半衰期。单细胞RNA测序还表明癌症不会诱导产生任何新的单核细胞群体。癌症不会改变骨髓中单核细胞祖细胞的数量，但单核细胞的增殖速率更高，从而解释了循环血液中单核细胞数量的增加。对这些单核细胞群体进行深度RNA测序发现，癌症会导致经典单核细胞区室发生变化，在骨髓单核细胞中变化明显，在血液中变化更为显著，这表明两个区室均受到影响，其中1型干扰素信号传导和抗原呈递的下调最为突出。与该分析结果一致，下调的基因在其启动子区域富含STAT1/STAT2结合位点，而STAT1/STAT2是1型干扰素信号传导所需的转录因子。然而，小鼠中的这些转录组变化并未重现乳腺癌患者中的情况。因此，这种乳腺癌小鼠模型可能不足以研究人类癌症的全身影响。
