Molecular Pharmacology and Therapeutics Graduate Program, University of Minnesota, 2231 6th St SE, Minneapolis, MN, 55455, USA.
University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.
Sci Rep. 2023 Apr 1;13(1):5349. doi: 10.1038/s41598-023-32321-0.
Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.
肿瘤细胞与肿瘤微环境之间的相互作用对于肿瘤的生长、进展和对治疗的反应至关重要。有效靶向肿瘤中的致癌信号通路需要了解这些疗法如何影响肿瘤细胞和肿瘤微环境中的细胞。Janus 激酶 (JAK)/信号转导和转录激活因子 (STAT) 通路就是这样一条通路，它在乳腺癌细胞和肿瘤相关巨噬细胞中均被激活。本研究表明，巨噬细胞暴露于 JAK 抑制剂会导致 NF-κB 信号的激活，从而导致与治疗耐药性相关的基因表达增加。此外，抑制 NF-κB 通路可提高鲁索替尼降低体内乳腺肿瘤生长的能力。因此，肿瘤微环境的影响是研究乳腺癌时需要考虑的一个重要因素，而了解这种耐药机制对于开发有效的靶向治疗至关重要。
