Tumor-associated macrophages (TAM) are among the most abundant immune cells in the tumor microenvironment and are important mediators of tumor development and progression. Here, we identified a macrophage-associated long non-coding RNA (lncRNA), MALR, that facilitates progression of esophageal squamous cell carcinoma (ESCC). TAM-mediated secretion of TNFα drove MALR upregulation in ESCC cells. MALR promoted aerobic glycolytic activity and facilitated angiogenesis by activating the HIF1α signaling pathway. Mechanistically, MALR bound the dsRBD1 domain of interleukin enhancer-binding factor 3 (ILF3), promoting ILF3 protein stability and ILF3-mediated liquid-liquid phase separation (LLPS), thereby enhancing HIF1α mRNA stability by preventing PARN-mediated degradation. Loss of MALR suppressed cell line-based and patient-derived xenograft tumor growth. Clinically, high expression of MALR positively correlated with HIF1α target gene expression and indicated poor prognoses for esophageal cancer patients. Overall, this study uncovers the physiological roles of MALR/ILF3-mediated LLPS in tumor microenvironment remodeling, highlighting the MALR-ILF3-HIF1α axis as a potential target for cancer therapy.
Background: Although numerous studies have investigated the clinicopathologic and prognostic relevance of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC) compared with classic adenocarcinoma (CA), little is known about the prognosis of adenocarcinoma with mixed subtypes (AM) and the differences among these four subtypes.
Methods: The statistics of colorectal cancer registered in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and analyzed. We also compared the clinicopathologic and prognostic relevance between CA, SRCC, MAC, and AM.
Results: The frequencies of these four subtypes were 69.9% (CA, n=15,812), 25.1% (MAC, n=5,689), 3.6% (SRCC, n=814) and 1.4% (AM, n=321), respectively. All of MAC, SRCC, and AM were significantly related with aggressive features. Only SRCC and AM were identified as independent poor prognostic markers for overall survival by multivariate analysis. The aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was significantly worse than MAC but comparable with SRCC.
Conclusion s: We confirmed the clinicopathologic relevance with aggressive features of MAC and SRCC, as well as poor prognostic relevance of SRCC by analyzing a large study population data set. Furthermore, we identified AM as a rare but aggressive histologic subtype in colorectal cancer, to which particular attention should be given in clinical practice.
Background: The outcomes of immune checkpoint inhibitors of patients with cancer liver metastases are poor, which may be related to a different tumor microenvironment from primary cancers. This study was aimed to analyze the PD-L1 expression and the immune microenvironment status in liver metastatic diseases and compare the differences of PD-L1 expression between primary tumors and liver metastases of colorectal cancer.Methods: 74 cases of pathologically confirmed colorectal cancer liver metastasis underwent resection from our hospital were included. Tissue microarrays were used for the interpretation of PD-L1 expression, cluster of differentiation 4 (CD4) and CD8 density by immunohistochemistry. Then, we evaluated the disparity between primary tumor and liver metastasis in PD-L1, CD4 and CD8 density and analyzed the factors associated with obvious disparity.Results: A total of 74 paired colorectal cancer with liver metastases were included in this study. The expression of PD-L1 in liver metastases was positively related to the density of CD4 and CD8. The expression of PD-L1 was higher in liver metastases than in primary tumors in certain subgroups of colorectal cancer, including the patients with concurrent liver metastases (n=63, p=0.05), receiving concurrent resection of primary and metastatic tumors (n=56, p=0.04). The two subgroups generally reflected those without inconsistent external influencing factors, such as treatment and temporal variation, between primary tumors and liver metastases. In these subgroups, the intrinsic differences of microenvironment between primary tumors and liver metastases could be identified, if any. Furthermore, tumor differentiation (moderate vs. poor: OR=0.23, 95% CI: 0.03-0.99, p=0.05)) were demonstrated to be associated with obvious discordance of PD-L1 expression between primary tumors and hepatic metastases.Conclusions: The expression of PD-L1 in the hepatic metastases was higher than in the primary tumors in subgroups reflecting intrinsic microenvironment differences between primary and metastatic tumors. Obvious discordance of PD-L1 expression between primary tumor and liver metastasis was closely related to the tumor differentiation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.