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Analysis of biological characterization and metastasis-related genes in cell lines derived from the Primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva

ABSTRACT: Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been many histological examinations of primary and metastatic lesions, but little basic research using cell strains from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell strain derived from lower gingival carcinoma (WK2) and a strain derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. We then investigated the biological characteristics of the cancer cell strains from these primary and metastatic lesions, and analyzed metastasis-related genes. Comparing the biological characteristics in vitro showed WK3F to have higher cell proliferation ability and shorter cell doubling time than WK2. It also showed increased cell migratory ability, and high invasive and self-replication abilities. Heterotransplantation into nude mice resulted in high tumor formation rates in the tongue and high metastasis rates in the cervical lymph nodes. Changes in WK2 and WK3F gene expression were comprehensively analyzed with the microarray method. Genes with increased expression in WK3F compared to WK2 were extracted when Z-score ≥ 2.0 and ratio ≥ 5.0, while genes with reduced expression in WK3F compared to WK2 were extracted when Z-score ≤ -2.0 and ratio ≤ 0.2. As a result, differences were found in 604 genes. From these, MAGEC1 (88.0 times), MMP-7 (18.6 times), SNAI1 (6.6 times), MACC1 (6.2 times), and HTRA1 (0.012 times) were selected as metastasis-related candidate genes. The results suggest that these molecules could be important to clarifying the mechanism of metastasis, and could become therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54672 | GEO | 2014/06/30

SECONDARY ACCESSION(S): PRJNA237332

REPOSITORIES: GEO

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Project description:Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been many histological examinations of primary and metastatic lesions, but little basic research using cell strains from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell strain derived from lower gingival carcinoma (WK2) and a strain derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. We then investigated the biological characteristics of the cancer cell strains from these primary and metastatic lesions, and analyzed metastasis-related genes. Comparing the biological characteristics in vitro showed WK3F to have higher cell proliferation ability and shorter cell doubling time than WK2. It also showed increased cell migratory ability, and high invasive and self-replication abilities. Heterotransplantation into nude mice resulted in high tumor formation rates in the tongue and high metastasis rates in the cervical lymph nodes. Changes in WK2 and WK3F gene expression were comprehensively analyzed with the microarray method. Genes with increased expression in WK3F compared to WK2 were extracted when Z-score ≥ 2.0 and ratio ≥ 5.0, while genes with reduced expression in WK3F compared to WK2 were extracted when Z-score ≤ -2.0 and ratio ≤ 0.2. As a result, differences were found in 604 genes. From these, MAGEC1 (88.0 times), MMP-7 (18.6 times), SNAI1 (6.6 times), MACC1 (6.2 times), and HTRA1 (0.012 times) were selected as metastasis-related candidate genes. The results suggest that these molecules could be important to clarifying the mechanism of metastasis, and could become therapeutic targets. We successfully established a cell strain derived from lower gingival carcinoma (WK2) and a strain derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. Changes in WK2 and WK3F gene expression were comprehensively analyzed with the microarray method.

Project description:Purpose: The overall survival rate for metastatic osteosarcoma hovers around 20%. Responses to second-line chemotherapy, targeted therapies, and immunotherapies have demonstrated limited efficacy in metastatic osteosarcoma. Our objective is to validate differentially expressed genes and signaling pathways between non-metastatic and metastatic osteosarcoma, employing single-cell RNA sequencing (scRNA-Seq) and additional functional investigations. We aim to enhance comprehension of metastatic mechanisms and potentially unveil a therapeutic target. Methods: scRNA-Seq was performed on two primary osteosarcoma lesions (1 non-metastatic and 1 metastatic). Uniform manifold approximation and projection (UMAP) facilitated dimensionality reduction and cluster identification. Copy number variation (CNV) was predicted using InferCNV. CellChat characterized ligand-receptor-based intercellular communication networks. Differentially expressed genes underwent GO function enrichment analysis and GSEA. Validation was achieved through the GSE 52048 dataset, which identified PDGFD-PDGFRB as a common ligand-receptor pair with significant contribution. Immunohistochemistry assessed PDGFD and PDGFRB expression, while multicolor immunofluorescence and flow cytometry provided insight into spatial relationships and the tumor immune microenvironment. Kaplan-Meier survival analysis compared metastasis-free survival and overall survival between high and low levels of PDGFD and PDGFRB. Manipulation of PDGFD expression in primary osteosarcoma cells examined invasion abilities and related markers. Results: Ten clusters encompassing osteoblasts, osteoclasts, osteocytes, fibroblasts, pericytes, endothelial cells, myeloid cells, T cells, B cells, and proliferating cells were identified. Osteoblasts, osteoclasts, and osteocytes exhibited heightened CNV levels. Ligand-receptor-based communication networks exposed significant fibroblast crosstalk with other cell types, and the PDGF signaling pathway was activated in non-metastatic osteosarcoma primary lesions. These results were corroborated by the GSE 52048 dataset, confirming the prominence of PDGFD-PDGFRB as a common ligand-receptor pair. Immunohistochemistry demonstrated considerably greater PDGFD expression in non-metastatic osteosarcoma tissue and organoids, correlating with extended metastasis-free and overall survival. PDGFRB expression showed no significant variation between non-metastatic and metastatic osteosarcoma, nor strong correlations with survival times. Multicolor immunofluorescence suggested co-localization of PDGFD with PDGFRB. Flow cytometry unveiled a highly immunosuppressive microenvironment in metastatic osteosarcoma. Manipulating PDGFD expression demonstrated altered invasive abilities and marker expressions in primary osteosarcoma cells from both non-metastatic and metastatic lesions. Conclusions: scRNA-Seq illuminated the activation of the PDGF signaling pathway in primary lesions of non-metastatic osteosarcoma. PDGFD displayed an inhibitory effect on osteosarcoma metastasis, likely through the suppression of the EMT signaling pathway.

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Analysis of biological characterization and metastasis-related genes in cell lines derived from the Primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva

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