Stroke Exacerbates Cancer Progression by Upregulating LCN2 in PMN-MDSC

Abstract

Acute ischemic stroke (AIS) is common in patients with cancer, and mounting clinical evidence suggests that it may shorten the survival of cancer patients. But how stroke affects the progression of cancer remains unclear. We inoculated B16 tumor cells (2 × 10 5 ) subcutaneously before distal middle cerebral artery occlusion (dMCAO) or sham surgery in C57BL/6 mice and found that compared to sham operated mice, dMCAO mice developed significantly increased tumor volume and were accompanied by lower survival rate. To explore the underlying mechanism, we performed RNA-sequencing analysis of the tumor tissue from mice with or without stroke and found prominent upregulation of lipocalin 2 (LCN2) in the tumor from stroke mice compared to those from sham mice. Using quantitative reverse transcription-PCR, we confirmed increased mRNA expression of LCN2 as well as anti-inflammatory cytokines-Arg1, IL-10, and decreased mRNA level of pro-inflammatory cytokines-IL-6, IL-23 in the tumor of cancer-bearing stroke mice. Both immunofluorescence staining and flow cytometry analysis revealed that increased expression of LCN2 was mainly derived from the polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) in the tumor. We also found that stroke reduced the PMN-MDSCs in the peripheral blood, but increased PMN-MDSCs in the tumor of the cancer-bearing mice after stroke. In conclusion, cerebral ischemic stroke may exacerbate cancer progression by increasing LCN2 expression in PMN-MDSCs, which turns out to be a promising therapeutic target to suppress cancer progression after ischemic stroke.

Lipocalin 2 upregulation mediates the detrimental effects of therapy-induced senescence in breast cancer cells

“…Moreover, consistent with observations from other groups, we show here that LCN2 expression leads to tumor progression in vivo (Chaudhary, 2021; Huang, 2020, Berger, 2010). Whether senescence-mediated LCN2 upregulation promotes metastasis of breast cancer remains to be elucidated.…”

Lipids in the tumor microenvironment: From cancer progression to treatment

“…Knocking out FATP2 results in the loss of PMN-MDSCs to suppress CD8+ T cells, implicating fatty acid uptake from the TME in PMN-MDSC tumor suppression [149]. Similar observations in PMN-MDSCs through other fatty acid transporters and binding proteins like CD36 [150] and Lipocalin 2 [151] have recently been reported. FAO may support immune suppression in PMN-MDSCs through ROS-produced peroxynitrite generation leading to T cell suppression [152].…”

Lipocalin-2 Mediated Polarization of Neutrophil in Cerebral Ischemia-Reperfusion Injury

“…We have also tested the expression of several in ammatory factors at the transcription level. According to the published literature, we have also explored and found that the antiin ammatory factor CD206 was increased, the pro-in ammatory factor TNF-was signi cantly reduced [38], while IL-10 and IL-1β had no obvious signs, which proved that LCN2 affects the transition of neutrophils and is accompanied by changes in in ammatory factors. But it may be is selective for the expression of in ammatory factors.…”