Johnson Catherine S, Costanzo-Garvey Diane, Valencia Julio C, Rajgopal Sanjana, Reed Theodore, Brannon Emma R, Frieling Jeremy S, Mosley Deanna D, Wyatt Todd A, Edmondson Elijah F, Mohan Kabhilan, Mathew Grinu, Cook Leah M
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.
Mol Cancer Res. 2025 Aug 4;23(8):739-758. doi: 10.1158/1541-7786.MCR-24-0672.
Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology and its impact in the tumor-bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of prostate cancer, co-injection of Cxcl1 knockout (KO) MSCs with bone-metastatic prostate cancer in bone significantly suppressed tumor growth compared with co-injection with scrambled control (non-targeting) MSCs, even in the presence of three times more prostate cancer to MSCs. Furthermore, bulk RNA sequencing revealed immune response pathways, both in Cxcl1-KO MSCs and bone-metastatic prostate cancer tumors containing Cxcl1-KO MSCs. In support of this, Cxcl1-KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 in bone-metastatic prostate cancer progression.
MSC-derived Cxcl1 regulates prostate cancer progression in bone.
尽管研究不断，但骨转移仍然是前列腺癌患者治疗中最大的挑战。在骨骼中，前列腺癌肿瘤劫持正常的骨重塑过程以推动癌症进展。然而，尚不清楚这些相互作用如何在骨环境中驱动骨转移性前列腺癌的生长。为了了解与骨转移性前列腺癌对间充质干细胞（MSC）调控相关的机制，我们之前发现骨转移性前列腺癌可诱导MSC表达促炎趋化因子CXCL8及其小鼠功能同源物Cxcl1。迄今为止，关于CXCL1/8在MSC生物学中的作用及其对肿瘤-骨环境的影响几乎没有相关信息。通过对Cxcl1进行基因敲除，我们发现Cxcl1/8在调节MSC向成骨细胞分化方面具有新作用，即靶向敲除Cxcl1可增强MSC的成骨细胞生成。尽管前列腺癌具有成骨性，但与注射乱序对照（非靶向）MSC相比，将Cxcl1基因敲除（KO）的MSC与骨转移性前列腺癌共同注射到骨中时，即使前列腺癌细胞数量是MSC的三倍，仍能显著抑制肿瘤生长。此外，批量RNA测序揭示了Cxcl1-KO MSC以及含有Cxcl1-KO MSC的骨转移性前列腺癌肿瘤中的免疫反应途径。为此，Cxcl1-KO MSC减少了骨环境中未成熟的中性粒细胞，同时增加了单核细胞。这些发现证明了MSC来源的Cxcl1在骨微环境中的重要性，并突出了Cxcl1在骨转移性前列腺癌进展中的重要性。
MSC来源的Cxcl1调节骨中前列腺癌的进展。
