Hypoxia and CD11b+ Cell Influx Are Strongly Associated With Lymph Node Metastasis of Oral Cancer

Sugiura, Kei; Nakajima, Shigeki; Kato, Ikuo; Okubo-Sato, Makiko; Nakazawa, Yasuo; Mitsudo, Kenji; Kioi, Mitomu

doi:10.21873/anticanres.14706

Cited by 6 publications

(8 citation statements)

References 21 publications

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“…Additionally, the recruited CD11b positive cells in hypoxia areas of the tumor have been reported to stimulate the lymphangiogenesis and lymph node metastasis in a glossectomy orthotopic mouse model of tongue cancer. 48 Similarly, our study also showed that the patients with an elevated NAR value pretreatment exhibited a high risk of regional recurrence. Moreover, peripheral neutrophils‐circulating tumor cells clusters have been reported to promote tumor progression in breast cancer.…”

Section: Discussionsupporting

confidence: 73%

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Neutrophil to apolipoprotein A‐I ratio as an independent indicator of locally advanced nasopharyngeal carcinoma

et al. 2021

Laryngoscope Investig Oto

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Purpose: To explore the peripheral blood cells (neutrophil/monocyte/lymphocyte/ platelet) to apolipoprotein AI or high-density lipoprotein-cholesterol ratio (NAR, MAR, LAR, PAR, NHR, MHR, LHR, and PHR) as independent prognostic indicators for stage III nasopharyngeal carcinoma (NPC).Patients and methods: Between 2009 and 2014, 562 patients diagnosed with stage III NPC who were treated with a concomitant chemotherapy and intensitymodulated radiotherapy with cumulative cisplatin dose ≥200 mg/m 2 were included in this retrospective study. Routine blood and biochemical variables and baseline clinical characteristics (T and N stage, age, sex, and induction chemotherapy) were collected. After inserting 19 hematological parameters into a set, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and restricted cubic splines regression to select valuable parameters for predicting 5-year overall survival (OS). Subsequently, univariate and multivariate survival analyses were used to assess independent indicators of 5-year OS, distant metastasis survival, regional recurrence-free survival (RRFS), and disease-free survival.Results: NAR, MAR, serum lactated dehydrogenase (LDH), and Epstein-Barr virus (EBV)-DNA were selected using LASSO regression, and the optimal cut-off values for NAR, MAR, EBV-DNA, and, LDH were 4.39, 0.3, 1590 copies/mL, and 218.4 IU/L, respectively. In multivariate survival analysis, higher NAR was associated with both poor 5-year OS and RRFS (hazard ratio [HR], 1.88; 95% confidence interval [CI],

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Section: Discussionsupporting

confidence: 73%

“…This then reduces the survival rate. Additionally, the recruited CD11b positive cells in hypoxia areas of the tumor have been reported to stimulate the lymphangiogenesis and lymph node metastasis in a glossectomy orthotopic mouse model of tongue cancer 48. T A B L E 2…”

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confidence: 99%

Neutrophil to apolipoprotein A‐I ratio as an independent indicator of locally advanced nasopharyngeal carcinoma

et al. 2021

Laryngoscope Investig Oto

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“…The occurrence of LNM in oral cancer patients usually predicts a poor prognosis [ 20 ]. Evidence has shown that hypoxia might result in the infiltration of relevant cells, including immune cells, in cancer tissues, which facilitates angiogenesis and thus expedites cancer metastasis [ 21 ]. In addition, hypoxia can induce the expression of relevant genes, and then stimulate cells to undergo the EMT through factors such as FGF1 , thereby promoting angiogenesis [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

<i>SERPINE1</i> as an Independent Prognostic Marker and Therapeutic Target for Nicotine-Related Oral Carcinoma

Guo

Sun

Chen

et al. 2023

Clin Exp Otorhinolaryngol

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Background: Nicotine is an ingredient of tobacco, and its exposure increases various cancer risks, including oral cancer. Previous studies have focused on its addictive properties, but its carcinogenic mechanism has rarely been studied. We aimed to explore the key genes in the process of nicotine promoting the occurrence and development of oral cancer through data mining and experimental verification. Methods: This study involved three parts. First, the key genes related to nicotine-related oral cancer were screened out through data mining; second, the expression and clinical significance of the key gene in oral cancer tissues were verified by bioinformatics. Finally, the expression and clinical significance of the key gene in oral cancer were histologically investigated, and the effects of its expression on cell proliferation, invasion, and drug resistance were cytologically assessed.Results: SERPINE1 was identified as the key gene, which was upregulated in nicotine-treated oral cells and may be an independent prognostic factor for oral cancer. SERPINE1 was enriched in various pathways such as TNF and Apelin pathways; and was related to the infiltration of macrophages, CD4+T cells, and CD8+T cells. Overexpression of SERPINE1 was associated with N staging and may be involved in hypoxia, angiogenesis, and metastasis. Knockdown of SERPINE1 in oral cancer cells resulted in weakened cell proliferation and invasion ability and increased sensitivity to Bleomycin and Docetaxel. Conclusion: This study revealed SERPINE1 as the key gene for nicotine-related oral cancer, indicating that SERPINE1 may be a novel prognostic indicator and therapeutic target for oral carcinoma.

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“…Next, we confirmed the cell migration ability in vivo. We established an orthotopic xenograft tongue tumor model in a prior study 24 . In this study, we implanted the EP4-overexpressing HSC-3 cells expressing green fluorescent protein (GFP) and luciferase into the tongues of mice, and determined the number of lymph node metastases with a fluorescence microscope and an in vivo bioluminescence imaging system (IVIS).…”

Section: Resultsmentioning

confidence: 99%

EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma

Ishikawa,

Umemura,

Nakakaji

et al. 2024

Commun Biol

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Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.

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Hypoxia and CD11b+ Cell Influx Are Strongly Associated With Lymph Node Metastasis of Oral Cancer

Cited by 6 publications

References 21 publications

Neutrophil to apolipoprotein A‐I ratio as an independent indicator of locally advanced nasopharyngeal carcinoma

Neutrophil to apolipoprotein A‐I ratio as an independent indicator of locally advanced nasopharyngeal carcinoma

<i>SERPINE1</i> as an Independent Prognostic Marker and Therapeutic Target for Nicotine-Related Oral Carcinoma

EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma

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