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BackgroundWe investigated whether CD24 (reportedly a stem cell marker and adhesion molecule) was expressed in regenerative mucosa in inflammatory bowel disease (IBD) and whether it could be functionally relevant.MethodsCD24 expression was examined in 10 cases of IBD and the relationship of CD24 with Wnt signaling was tested using dominant negative (DN)-TCF4 expression. For functional evaluation, CD24 was 1) cloned and forcibly expressed in HCT116 (which expresses very low levels of CD24) and 2) knocked-down by RNA interference in HT29 (which expresses high levels of CD24). The effect of altered CD24 expression on proliferation/apoptosis, staurosporine-induced apoptosis, colony formation in soft agar, migration, and invasion was examined.ResultsCD24 was not expressed in normal tissue, while 10/10 cases of IBD showed CD24 upregulation. Inhibition of Wnt signaling with DN-TCF4 caused CD24 downregulation. Forced expression of CD24 did not influence cell proliferation, apoptosis, or staurosporine-induced apoptosis but it did significantly enhance colony forming efficiency (P < 0.01). Furthermore, there was increased transwell migration (P < 0.001) and invasion (P < 0.03) and there was increased cell migration in wounding assays. Conversely, knockdown of CD24 reduced transwell migration (P < 0.01) and invasion (P < 0.01) and reduced cell motility in wounding assays. CD24 knockdown did not influence proliferation, apoptosis resistance, or staurosporine-induced apoptosis.ConclusionsThis is the first study to report upregulation of CD24 in regenerating tissue in IBD. This may be regulated by Wnt signaling and can confer enhanced colony forming ability and enhanced cell motility—features that may be important in tissue healing in the colon. Inflamm Bowel Dis 2010

Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P  = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor–positive subgroup. There was no correlation between CD24 3′UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.

CD44/CD24 and ALDH1 are widely used cancer stem cell (CSC) markers in breast cancer. However, their expression is not always consistent even in the same subtype of breast cancer. Systematic comparison of their functions is still lacking. We investigated the expression of CD44, CD24 and ALDH1 in different subtypes of breast cancer cells, and explored their relationship with cancer progression. We defined a parameter CD44/CD24 ratio to present the expression level of CD44 and CD24 and found that high CD44/CD24 ratio and ALDH1 + are both indicators for cancer malignancy, but play different functions during tumor progression. High CD44/CD24 ratio is more related to cell proliferation and tumorigenesis, which is confirmed by mammosphere formation and tumorigenesis in xenotransplanted mice. ALDH1 + is a stronger indicator for cell migration and tumor metastasis. Suppression of CD44 and ALDH1 by siRNA led to decreased tumorigenicity and cell migration capacity. The combination of high CD44/CD24 ratio and ALDH1 + would be a more reliable way to characterize CSCs. Moreover, both high CD44/CD24 ratio and ALDH1 + were conserved during metastasis, from the primary tumors to the circulating tumor cells (CTCs) and the distant metastases, suggesting the significant value of these CSC markers in assisting cancer detection, prognostic evaluation, and even cancer therapeutics.

The transcription factors Batf3 and IRF8 are required for the development of CD8α + conventional dendritic cells (cDCs). Murphy and colleagues characterize the Batf3-IRF8 interactions that allow differentiation toward CD8α + cDCs. The transcription factors Batf3 and IRF8 are required for the development of CD8α + conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α + cDCs and CD4 + cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α + cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α + cDC–specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3 −/− mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α + cDCs due to decay of Irf8 autoactivation and diverted to the CD4 + cDC lineage.

Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8 + T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency. Blockade of CD47/SIRPα and CD24/Siglec-10 pathways can promote macrophage-mediated phagocytosis of tumor cells. Here the authors report the design of a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor that enhances the phagocytic ability of macrophages and improves response to anti-PD-1 in preclinical cancer models.

The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24⁺CD133⁺ LCSCs, but not CD24⁻CD133⁻ LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24⁺CD133⁺ LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24⁺CD133⁺ HCC.

Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, and CD44-CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+CD24- human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.

Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our results indicate that dual-phagocytosis checkpoint blockade offers a promising therapeutic avenue to potentiate cancer immunotherapy. Macrophage-dependent phagocytosis elicits robust antitumor immunity. Nevertheless, therapeutic strategies harnessing phagocytosis have been met with limited success. Here the authors demonstrate that dual-phagocytosis checkpoint blockade, achieved by simultaneously targeting CD47 and CD24, greatly enhances tumor cell phagocytosis thus increasing antigen-presentation capacity, cGAS-STING activation and T cell infiltration into the tumor microenvironment, ultimately fostering robust antitumor immunity in preclinical mouse models of glioblastoma.

CD24 promotes prostate cancer progression and metastasis by disrupting the ARF-NPM interaction and impairing p53 signaling. However, the mechanisms underlying CD24-driven metastasis remain unclear. This study identifies a novel interaction between CD24 and Regulator of Chromosome Condensation 2 (RCC2), a protein involved in cell proliferation and migration. IHC analysis of prostate adenocarcinoma samples showed frequent coexpression of CD24 (49%) and RCC2 (82%) with a positive correlation between coexpression of CD24 (49%) and RCC2 (82%). Functional assays revealed complex roles: RCC2 KO suppressed proliferation but increased migration and invasion, while CD24 KO reduced both proliferation and migration. Dual KO of CD24 and RCC2 further inhibited proliferation but had varied effects on migration. In mouse xenografts, RCC2 KO increased lung metastasis without significantly affecting primary tumor growth, while CD24 KO reduced both tumor growth and metastasis. Mechanistically, RCC2 controls migration by promoting ubiquitination and degradation of vimentin, affecting cytoskeletal dynamics. In contrast, CD24 targets RCC2 for degradation, thereby regulating β-catenin signaling. Notably, RCC2 KO enhances β-catenin activity by suppressing inhibitors AXIN2 and APC, whereas CD24 KO inhibits this pathway. These findings reveal a regulatory loop where CD24 and RCC2 reciprocally control proliferation and metastasis, positioning the CD24-RCC2 axis as a promising therapeutic target in prostate cancer.

Exosomes are small membrane vesicles that are secreted from a variety of cell types into various body fluids including the blood and urine. These vesicles are thought to play a role in cell–cell interactions. CD24 is a small but extensively glycosylated protein linked to the cell surface by means of a glycosyl-phosphatidylinositol anchor. In this study we found that CD24 is present in membrane vesicles characterized as exosomes that were isolated from the urine of normal individuals. CD24 was expressed by both tubule cells and podocytes and treatment of the latter with a cholesterol-extracting agent, but not with a calcium ionophore, caused the release of CD24-containing exosomes. Using CD24 as a marker, we found exosomes in the urine of newborn infants and in the amniotic fluid of pregnant women with similar findings made in mice. Interestingly, studies with CD24 knockout mice showed that the exosomes are released from the fetus but not from the mother; however, exosome release was similar from both the knockout and the wild-type mice. This indicates that CD24 is not essential for exosome formation or release but may be a convenient exosome marker. Our studies suggest that exosomal secretion from the embryonic kidney could play a biological role at the fetal–maternal interphase.