Dataset Information

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

ABSTRACT: Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1's involvement in the chemo-resistance of cancer cells was suggested.

SUBMITTER: Matsubara E

PROVIDER: S-EPMC9496817 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Matsubara Eri E Komohara Yoshihiro Y Esumi Shigeyuki S Shinchi Yusuke Y Ishizuka Shiho S Mito Remi R Pan Cheng C Yano Hiromu H Kobayashi Daiki D Fujiwara Yukio Y Ikeda Koei K Sakagami Takuro T Suzuki Makoto M

Cancers 20220908 18

Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). T ...[more]

PMID: 36139536

Similar Datasets

Project description:BackgroundSecreted phosphoprotein 1 (SPP1), an extracellular secreted glycol phosphoprotein, is closely related to tumor biologies, such as proliferation, migration, and invasion. However, the role and biological function of SPP1 in lung adenocarcinoma (LUAD) was still ambiguous.MethodsSPP1 expression in LUAD tissues and its associations with clinical features and prognosis was investigated using meta-analysis, immunohistochemistry (IHC) staining methods, and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the potential mechanism related to SPP1 was identified by using the Gene Set Enrichment Analysis (GSEA) method. A series of function assays were conducted to determine the biological role of SPP1 in LUAD cell migration and invasion in vitro and vivo. The co-expressed genes of SPP1 were obtained and verified by western blot assays. The influence of SPP1 on Collagen type XI alpha 1 (COL11A1) expression and epithelial-mesenchymal transition (EMT) markers was analyzed using western blot assays.ResultsThe expression of SPP1 in LUAD tissues and cells was significantly higher than that in normal tissues and cells. And positively associations of SPP1 expression with TNM stage, lymph node metastasis, and invasion depth were observed. Patients with high SPP1 expression had unfavorable survival. The multivariable Cox regression analysis revealed that SPP1 expression was an independent prognostic factor of LUAD patients. Furthermore, downregulation of SPP1 could inhibit cell migration and invasion both in vitro and vivo, reduce the expression of epithelial marker (E-cadherin), and increase the expression of mesenchymal markers (N-cadherin and vimentin). Using bioinformatics and western blot assays, we confirmed that COL11A1 acted as the downstream of SPP1, and SPP1 knockdown could significantly downregulate the COL11A1 expression. Importantly, suppression of cell migration and invasion and the expression changes of EMT markers induced by SPP1 downregulation could be reversed by COL11A1 overexpression.ConclusionsSPP1 facilitates cell migration and invasion by upregulating COL11A1 expression and that acts as a potential biomarker of metastasis and prognosis for LUAD.

Project description:5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent with APRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013].A combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.

Project description:BackgroundThe tumor microenvironment (TME) is highly associated with cancer stem cells, and affects tumor initiation, progression, and metastasis. This study aimed to explore the underlying molecular mechanism of induction of A549 cancer cell stemness by THP-1-derived macrophages.MethodThe Hedgehog inhibitor (Vismodegib), Notch inhibitor Gamma Secretase Inhibitor (GSI), and Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor Cucurbitacin I (JSI-124) were added separately into the co-culture system of A549 cancer cell with THP-1-derived macrophages. Cell Counting Kit-8 (CCK-8) assay and the Cell-IQ continuous surveillance system were used to examine the cell growth and morphological changes of A549 cells. The messenger ribonucleic acid (mRNA) and protein expression levels of stem cell markers were respectively analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, and the activity of Acetaldehyde dehydrogenase (ALDH) enzyme was assessed by flow cytometry analysis. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR assays were performed to evaluate the activation and differentiation of macrophages.ResultsResults showed that the proliferation and stemness of A549 cells were significantly enhanced by co-culturing with THP-1-derived macrophages. The expression levels of Transforming growth factor-β (TGF-β) and Interleukin-6 (IL-6) in macrophages were notably increased after co-culturing with A549 cells. Meanwhile, co-culturing with A549 cells induced the polarization of macrophages towards the M2 phenotype. Moreover, the inhibitors could reduce the proliferation and stemness of the co-culture system, and decrease the expression of TGF-β and IL-6.ConclusionsThese results suggested that co-culturing A549 cells with THP-1-derived macrophages could induce the stemness of A549 cells via multiple pro-tumorigenic pathways. Thus, inhibition of the interaction between macrophages and lung cancer stem cells may be a viable target for lung cancer treatment in the future.

Dataset Information

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Publications

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets