Neoplasia最新文献

{"title":"XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling","authors":"Jieun Ahn,&nbsp;Seung-Hun Jang,&nbsp;Sungchan Jang,&nbsp;Ji-Hye Yoon,&nbsp;Min-Goo Lee,&nbsp;Sung-Gil Chi","doi":"10.1016/j.neo.2024.101094","DOIUrl":"10.1016/j.neo.2024.101094","url":null,"abstract":"<div><div>X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span>, tumor necrosis factor <span><math><mrow><mo>−</mo><mi>α</mi></mrow></math></span>, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span> injection, <em>Xaf1</em>^<em>+</em>^<em>/+</em> tumors display significantly higher regression rate and T cell infiltration compared to <em>Xaf1^−/−</em> tumors while <em>Xaf1</em>^−/− tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101094"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents","authors":"Rocco Caggiano ,&nbsp;Evgeniia Prokhorova ,&nbsp;Lena Duma ,&nbsp;Kira Schützenhofer ,&nbsp;Raffaella Lauro ,&nbsp;Giuliana Catara ,&nbsp;Rosa Marina Melillo ,&nbsp;Angela Celetti ,&nbsp;Rebecca Smith ,&nbsp;S John Weroha ,&nbsp;Scott H Kaufmann ,&nbsp;Ivan Ahel ,&nbsp;Luca Palazzo","doi":"10.1016/j.neo.2024.101092","DOIUrl":"10.1016/j.neo.2024.101092","url":null,"abstract":"<div><div>The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. <em>ARH3</em> knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in <em>ARH3</em>-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101092"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPM4 overexpression drives colon epithelial cell tumorigenesis by suppressing differentiation and promoting proliferation","authors":"Rajsumeet S. Macwan ,&nbsp;Giulio Ferrero ,&nbsp;Barbara Pardini ,&nbsp;Alessio Naccarati ,&nbsp;Piotr B. Kozlowski ,&nbsp;Michael J. Papetti","doi":"10.1016/j.neo.2024.101093","DOIUrl":"10.1016/j.neo.2024.101093","url":null,"abstract":"<div><h3>Objective</h3><div>The high morbidity and mortality associated with colorectal cancer (CRC) and the recent increases in early-onset CRC obviate the need for novel methods to detect and treat this disease, particularly at early stages. We hypothesize that aberrant expression of genes involved in the crypt-luminal migration of colon epithelial cells, a process necessary for their growth arrest and maturation, may disrupt differentiation and transition cells from a normal to tumorigenic state.</div></div><div><h3>Methods</h3><div>We searched for contractility- and motility-related genes that are dysregulated in human CRC relative to normal colon. RNA expression of one such gene, tropomyosin 4 (<em>TPM4</em>), was measured by qRT-PCR and RNA-seq in human colorectal tissues at various stages of tumorigenesis: CRC, adenoma, and at-risk (grossly normal mucosa from a patient with Familial Adenomatous Polyposis, or FAP), relative to controls. Effects of aberrant <em>TPM4</em> expression on colon epithelial cell proliferation and maturation were determined by overexpression using stable transfection in spontaneously differentiating Caco2 cells or silencing using siRNA in proliferating cells.</div></div><div><h3>Results</h3><div><em>TPM4</em> is overexpressed at various stages of tumorigenesis, including CRC, adenoma, and grossly normal FAP colon tissue, as well as in proliferating versus differentiating Caco2 cells. <em>TPM4.2</em> overexpression in differentiating Caco2 cells markedly inhibits certain aspects of maturation, notably sucrase isomaltase and glutathione-S-transferase alpha1 expression, and causes morphological and cell junction abnormalities. Conversely, siRNA-mediated suppression of <em>TPM4.2</em> inhibits Caco2 proliferation.</div></div><div><h3>Conclusions</h3><div><em>TPM4</em> overexpression attenuates colon epithelial cell differentiation and promotes proliferation. Therefore, <em>TPM4</em> expression may be a biomarker to enhance strategies for CRC diagnosis and treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101093"},"PeriodicalIF":4.8,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells","authors":"Adrian Fehn ,&nbsp;Adrian von Witzleben ,&nbsp;Ayla Grages ,&nbsp;Tsima Abou Kors ,&nbsp;Jasmin Ezić ,&nbsp;Annika C. Betzler ,&nbsp;Cornelia Brunner ,&nbsp;Patrick J. Schuler ,&nbsp;Marie-Nicole Theodoraki ,&nbsp;Thomas K. Hoffmann ,&nbsp;Simon Laban","doi":"10.1016/j.neo.2024.101086","DOIUrl":"10.1016/j.neo.2024.101086","url":null,"abstract":"<div><div>Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.</div><div>We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.</div><div>In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.</div><div>DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101086"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and function of the lysine methyltransferase SETD2 in cancer: From histones to cytoskeleton","authors":"Christina Michail,&nbsp;Fernando Rodrigues Lima,&nbsp;Mireille Viguier,&nbsp;Frédérique Deshayes","doi":"10.1016/j.neo.2024.101090","DOIUrl":"10.1016/j.neo.2024.101090","url":null,"abstract":"<div><div>SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.</div><div>Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of \"non-epigenetic/H3K36me3\" functions of SETD2 in cancer, particularly those involving the cytoskeleton.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101090"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early separation and parallel clonal selection of dedifferentiated and well-differentiated components in dedifferentiated liposarcoma","authors":"Tetsuya Sekita ,&nbsp;Naofumi Asano ,&nbsp;Takashi Kubo ,&nbsp;Hirohiko Totsuka ,&nbsp;Sachiyo Mitani ,&nbsp;Naoko Hattori ,&nbsp;Akihiko Yoshida ,&nbsp;Eisuke Kobayashi ,&nbsp;Motokiyo Komiyama ,&nbsp;Toshikazu Ushijima ,&nbsp;Robert Nakayama ,&nbsp;Masaya Nakamura ,&nbsp;Akira Kawai ,&nbsp;Hitoshi Ichikawa","doi":"10.1016/j.neo.2024.101074","DOIUrl":"10.1016/j.neo.2024.101074","url":null,"abstract":"<div><div>Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101074"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48Cre/+-LSL-KrasG12D/+ Mice” [Neoplasia, Volume 14, Issue 9 (2012) 778-787]","authors":"Chinthalapally V Rao ,&nbsp;Altaf Mohammed ,&nbsp;Naveena B Janakiram ,&nbsp;Qian Li ,&nbsp;Rebekah L Ritchie ,&nbsp;Stan Lightfoot ,&nbsp;Awasthi Vibhudutta ,&nbsp;Vernon E Steele","doi":"10.1016/j.neo.2024.101081","DOIUrl":"10.1016/j.neo.2024.101081","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101081"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depletion of regulatory T cells enhances the T cell response induced by the neoantigen vaccine with weak immunogenicity","authors":"Ruichen Huang ,&nbsp;Qiao Zhou ,&nbsp;Jiajun Liu ,&nbsp;Yang Xia ,&nbsp;Yang Jiao ,&nbsp;Bi Zhao ,&nbsp;Tangtao Feng ,&nbsp;Haosu Zhou ,&nbsp;Xiuyan Song ,&nbsp;Hao Qin ,&nbsp;Jun Wang ,&nbsp;Lan Cheng ,&nbsp;Yunye Ning ,&nbsp;Qinying Sun ,&nbsp;Yanfang Liu ,&nbsp;Xiaoping Su ,&nbsp;Yuchao Dong ,&nbsp;Wei Zhang","doi":"10.1016/j.neo.2024.101088","DOIUrl":"10.1016/j.neo.2024.101088","url":null,"abstract":"<div><h3>Background</h3><div>The neoantigen vaccine has remarkable potential in treating advanced cancer due to its tumor specificity and ability to bypass central tolerance mechanisms. However, numerous neoantigens show poor immunogenicity, and the immune inhibitory factors of present in both tumors and tumor-draining lymph nodes impair the efficacy of cancer neoantigen vaccine. Eliminating immunosuppressive cells will improve the priming and expansion of anti-tumor immune cells induced by the vaccine.</div></div><div><h3>Methods</h3><div>In this study, a Treg-depleting regimen (consisting of CD25mAb and low-dose cyclophosphamide (LD-CTX)) was used in conjunction with a neoantigen vaccine for treating mice with solid tumors. We constructed two types of tumor models and investigated differences in therapy efficacy in the four groups (PBS, vaccine, CD25mAb+CTX and combination) at the genetic and protein levels. ELISPOT and TCR sequencing were applied to detect the expansion of neoantigen reactive T cells (NRT) and tumor antigen spreading.</div></div><div><h3>Results</h3><div>In the combinational group, the ELISPOT results showed an obvious expansion of NRT cells induced by weak immunogenic peptides. The combinational group exhibited significant improvement in inhibiting the tumor growth extended the survival time of tumor-bearing mice, and promoted T cells infiltration into tumors. Besides, compared to the Vac group, more neoantigen-targeted and TAA-targeted T cells were detected in the combinational group by TCR sequencing. The results of transcriptomic sequencing and flow cytometry showed that the number of Tregs in the combinational group was lower, while the proportions of memory effector T cells and effector T cells were higher than those in the vaccine group. An increase in mature DCs was also observed in vaccinated mice after receiving this Treg-depleting strategy.</div></div><div><h3>Conclusion</h3><div>Our research first revealed that inhibiting the normal function of Tregs transformed “weaker” neoantigens into “stronger” ones, while also contributing to the proliferation of NRT cells. This Treg-depleting strategy allowed neoantigens with poor immunogenicity to elicit a robust immune response, thereby augmenting the efficacy of the neoantigen vaccine in delaying tumor growth and prolonging the survival of the hosts.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101088"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering and characterization of Hu3A4: A novel humanized antibody with potential as a therapeutic agent against myeloid lineage leukemias","authors":"Sisi Li ,&nbsp;Zhujun Wang ,&nbsp;Xiaoping Guo ,&nbsp;Yongmin Tang","doi":"10.1016/j.neo.2024.101084","DOIUrl":"10.1016/j.neo.2024.101084","url":null,"abstract":"<div><div>Leukemia stem cells (LSCs) play a critical role in the initiation, recurrence, and resistance to treatment of leukemia. Eradicating LSCs is crucial for the complete elimination of the disease. CD45RA is identified as an important marker for LSC subsets in acute myeloid leukemia (AML), providing a strategic target for therapy. In this report, we introduce Hu3A4, an innovative humanized CD45RA antibody devised to target LSCs expressing this antigen. Hu3A4 retains the antigen-recognition ability of its parental antibody while removing sequences from the variable region that could elicit human anti-mouse immune reactions. The modified variable regions of the heavy and light chains were intricately fused with the constant regions of human IgG1 heavy and light chains, respectively, producing a humanized antibody that emulates the structure of natural IgG. Hu3A4 was produced through recombinant expression in Chinese Hamster Ovary (CHO) cells, which ensured stable gene integration. In vitro tests revealed that Hu3A4 could effectively target and lyse the cells. Further, in vivo studies highlighted Hu3A4′s substantial anti-leukemic activity, significantly prolonging survival times in treated animal models compared to controls (P &lt; 0.01). To summarize, Hu3A4 exhibits remarkable bioactivity and offers a promising therapeutic potential for the treatment of leukemia patients. Progressing Hu3A4 through additional preclinical and clinical studies is crucial to validate its efficacy as a therapeutic agent for leukemia.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101084"},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-redundant roles of the CCR1 and CCR2 chemokine axes in monocyte recruitment during lung metastasis","authors":"Alessia G. Liner ,&nbsp;Merel van Gogh ,&nbsp;Marko Roblek ,&nbsp;Matthias Heikenwalder ,&nbsp;Lubor Borsig","doi":"10.1016/j.neo.2024.101089","DOIUrl":"10.1016/j.neo.2024.101089","url":null,"abstract":"<div><div>Monocytes and monocyte-derived macrophages facilitate cancer progression and metastasis. Inflammatory monocytes expressing CCR2 are actively recruited to metastatic lungs, where they promote tumor cell extravasation, metastatic outgrowth, and an immunosuppressive environment. The role of CCR1 in this process has remained unclear. We used Ccr1- and Ccr2-deficient mice and two different tumor cells lines, MC38 and LLC1 with and without Ccl2-deficiency <em>in vitro</em> and <em>in vivo</em>. The recruitment of both Ccr1- and Ccr2-deficient monocytes towards the Ccl2 chemokine was significantly impaired, while no substantial recruitment was observed towards Ccl5 <em>in vitro</em>. MC38 and LLC1 Ccl2-deficient tumor cells showed reduced lung metastasis in both Ccr1- and Ccr2-deficient mice when compared to wild-type mice. We detected reduced numbers of macrophages and myeloid cells in both chemokine receptor-deficient mice. Lung metastasis in both Ccr1- and Ccr2-deficient mice could be rescued to the same levels as in wild-type mice by an adoptive transfer of Ccr2-deficient but not Ccr1-deficient monocytic cells. Accumulation of Ccr1-deficient monocytes in the lungs was severely impaired upon intravenous monocyte injection, indicating the importance of this axis in cell recruitment. Moreover, the efficient recruitment of adoptive transferred Ccr2-deficient monocytes to the lungs and the restoration of lung metastasis suggests an involvement of an additional, Ccr2-independent chemokine pathway. This data defines the non-redundant functions of the Ccr1- and Ccr2-chemokine axes in monocyte recruitment and macrophage presence during lung metastasis. While Ccr2 is essential for the release of monocytes from the bone marrow, Ccr1 is primarily responsible for monocyte presence at metastatic sites.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101089"},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}