Metastasis Of Adenoid Cystic Carcinoma Research Articles

Surgical management of patients with distant metastasized adenoid cystic carcinoma of the head and neck

Background: Adenoid cystic carcinoma (ACC) is a rare and malignant tumor of the salivary glands. Despite its slow-growing nature, this clinical entity is notorious for presenting with distant metastasis (DM) which significantly worsens patient outcomes. The role of surgery in patients with ACC and distant metastasis (DM) remains controversial. Methods: We conducted a retrospective analysis of 47 patients with ACC who underwent surgery for the primary tumor and presented with DM at baseline or developed DM during follow-up. We compared survival outcomes between patients with DM at baseline (Group A) and those who developed DM during follow-up (Group B). Results: The median overall survival (OS) for the entire cohort was 88%. Patients with DM at baseline (Group A) had significantly worse OS (51%) compared to those without DM at baseline (Group B) (91%; p=0.04). Local recurrence (LR) was associated with poor survival in both groups. However, salvage surgery for LR+DM was associated with improved OS compared to palliative treatment (100% vs 77%; p=0.79). Conclusion: Our findings suggest that surgery for the primary tumor of ACC may provide survival benefits in patients with DM. Salvage surgery should be considered particularly for patients who develop local recurrence and distant metastasis during follow-up.

Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for β-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that β-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/β-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.

Adenoid cystic carcinoma metastatic to the kidney: a series of 10 patients emphasizing unilateral presentation and long time interval from primary diagnosis.

Adenoid cystic carcinoma (AdCC) metastasis to kidney is rare. We identified 10 patients with metastatic AdCC in multi-institutional collaboration. Core needle biopsy was the most common specimen (n = 6). Patients were predominately female (n = 7) with a median age of 48years (35-62years). The most common primary location of the AdCC was head and neck (n = 6, among them parotid gland = 4), followed by lung (n = 2), breast (n = 1), and vulva (n = 1). Median lapse between primary AdCC and renal metastasis was almost 13years (154months, range 1-336months). Moreover, all but one patient had unilateral kidney metastasis. The majority of metastatic AdCC within the kidney demonstrated mixed growth patterns, frequently cribriform, and tubular morphology. Follow-up available for 8 patients showed 6 alive with disease and 2 died of disease (the longest survival was 4years past the diagnosis of renal metastasis). A systematic literature review including 29 patients revealed that kidney metastasis by AdCC is usually a late event, is typically unilateral, and is usually composed of one to three foci, and thus has clinical features which mimic a primary renal tumor.

The Role of Parotid Gland Invasion in Adenoid Cystic Carcinoma of the External Auditory Canal.

This study aimed to investigate the significance of parotid gland invasion in predicting distant metastasis of adenoid cystic carcinoma in the external auditory canal. Single-institution retrospective cohort study. A retrospective review of patients with adenoid cystic carcinoma of the external auditory canal who underwent surgery was performed. Information on patient demographics, parotid gland invasion, tumor stage, perineural invasion, lymphovascular invasion, and follow-up data were collected and analyzed. One hundred twenty-nine patients were identified for review. Parotid gland invasion was noted in 45 patients (34.9%). Parotid gland invasion was significantly associated with tumor stage, perineural invasion, distant metastasis, and postoperative adjuvant therapy. Distant metastasis was noted in 30 patients (23.3%). Multivariate Cox proportional hazards analysis identified parotid gland invasion as an independent risk factor for predicting distant metastasis. The 5-year distant metastasis-free survival rate was 83.6% for patients without parotid gland invasion and 61.8% for patients with parotid gland invasion (p = 0.010). The parotid gland invasion rate is relatively high in adenoid cystic carcinoma of the external auditory canal and is significantly related to tumor stage. Parotid gland invasion is associated with worse distant metastasis-free survival. 4 Laryngoscope, 134:419-425, 2024.

Surgical treatment of thoracic metastases of adenoid cystic carcinoma of the base of the tongue: a case report

Surgical treatment of thoracic metastases of adenoid cystic carcinoma of the base of the tongue: a case report

NKT cells contribute to alleviating lung metastasis in adenoid cystic carcinoma

AbstractSalivary adenoid cystic carcinoma (SACC) with a unique MYB‐NFIB fusion has been considered an “immune‐cold” tumor, but the mechanisms behind this remain unclear. In this study, we analyzed the immune status of 29 SACC patients and found that most lung metastases exhibited an immunoinflammatory state, in contrast to the primary SACC tissues. Single‐cell sequencing data showed that anergic T‐cell types were low in primary inflammatory tissues, while inflammatory metastatic lung tissues had elevated levels of anergic CD8+ natural killer T (NKT)‐like cells and low levels of memory T cells. Primary exclusive tissues had high levels of myeloid‐derived suppressor cells (MDSCs) and low levels of activated CD8+ NKT‐like cells. These data support the fact that metastatic SACC cells might induce a stronger immune response in the lung. Additionally, an in vivo experiment showed that a minimally invasive SACC cell line with higher expression of human leukocyte antigens ‐B and ‐C induced NKT cell activation in mice and effectively attenuated the incidence of lung metastases caused by a highly invasive SACC cell line. This suggests that NKT therapy may be active in treating SACC lung metastasis. Conclusively, this study sheds light on the immune microenvironment of SACC and highlights the potential of NKT‐based therapy.

Does Multimodal Treatment Improve Eye and Life Salvage in Adenoid Cystic Carcinoma of the Lacrimal Gland?

To evaluate the efficacy of multimodal treatment in adenoid cystic carcinoma (ACC) of the lacrimal gland. A retrospective comparative case series of 40 consecutive patients with ACC of the lacrimal gland without systemic metastasis at the initial presentation and primarily managed by one of the 3 treatment protocols-surgery + external beam radiotherapy (EBRT) (group 1), surgery + EBRT + adjuvant chemotherapy (group 2), and neoadjuvant chemotherapy + surgery + EBRT + adjuvant chemotherapy (multimodal treatment) (group 3) at a tertiary care ocular oncology center. Local tumor control, eye salvage, and systemic metastasis were the primary outcome measures. The age ranged from 11 to 72 (mean ± SD, 36 ± 13; median, 36) years with 26 (65%) male and 14 (35%) female patients. Twelve (30%) patients belonged to group 1, 8 (20%) to group 2, and 20 (50%) to group 3. Primary surgery included tumor excision in 36 (90%) and orbital exenteration in 4 (10%). Chemotherapy composed of cisplatin + 5 fluorouracil (5FU) for 6 cycles in 28 (70%) patients. Extended-field stereotactic EBRT with a dose of 5,000-6,000 cGy included the entire pretreatment extent of the tumor with a 10-mm margin all around, superior orbital fissure, inferior orbital fissure, cavernous sinus, and temporal fossa. Mean duration of follow up after completion of treatment was 58 ± 26 (range, 29-180; median, 60) months. In all, local tumor recurrence occurred in 10 (25%) patients at a mean of 38 ± 23 (range, 12-120; median, 24) months. Local tumor recurrence was noted in 5 (42%) patients in group 1, 2 (25%) in group 2, and 3 (15%) in group 3. Overall, eye salvage was possible in 34 (85%) patients, with visual acuity >20/40 in 28 (82%). Systemic metastasis occurred in 10 (25%) patients at a mean of 53 ± 28 (range, 12-120; median, 43) months. Eight (67%) patients in group 1, 1 (13%) in group 2, and 1 (5%) in group 3 developed systemic metastasis. Six (15%) overall, 5 (42%) in group 1 and 1 (13%) in group 2, died with systemic metastasis. Multimodal treatment with sequential neoadjuvant chemotherapy, followed by surgery, extended-field stereotactic EBRT, and adjuvant chemotherapy seems relatively more effective in providing local tumor control and eye salvage and in minimizing the risk of systemic metastasis in ACC of the lacrimal gland.

Cutaneous metastasis of adenoid cystic carcinoma with high‐grade transformation: A case presentation

Cutaneous metastasis of adenoid cystic carcinoma with high‐grade transformation: A case presentation

Treatment and survival outcomes of ceruminous carcinomas of the external auditory canal: a SEER database analysis and literature review.

Ceruminous carcinomas of the external auditory canal (EAC), encompassing adenoid cystic carcinoma (ACC), ceruminous adenocarcinoma (CA), and mucoepidermoid carcinoma (MEC), are extremely rare with little known regarding the influence of demographics, tumor characteristics, and treatment on survival. This study aimed to summarize existent data and describe prognostic factors affecting survival in ceruminous carcinoma. Cases of ceruminous carcinoma of the EAC in the Surveillance, Epidemiology, and End Results (SEER) database were analyzed to provide demographic, cancer-related, and treatment data and assess their influence on disease-specific and overall survival. A literature review was alsoperformed. No significant difference in overall survival (OS) existed for localized versus regional disease, tumor type, or use of radiation therapy. In those with ACC, distant disease had a lower OS compared to regional disease. On review of the literature, local recurrence was a common finding with a low risk for nodal metastasis in ACC and CA. In conclusion,local recurrence wascommondespite aggressive surgical intervention (± radiation therapy); overall survival was unaffected by radiation therapy, tumor type, or local versus regional disease; and more cases of MEC are needed for analysis.

Survival Analysis of 76 Cases of Head and Neck Adenoid Cystic Carcinoma with Lung Metastasis

背景与目的头颈部腺样囊性癌（adenoid cystic carcinoma, ACC）常发生肺转移，目前ACC肺转移的研究报道不多，对于其确切的临床特征和治疗结果知之甚少，最佳治疗策略尚无共识。本研究探讨头颈部ACC肺转移的有效治疗策略、临床结局和长期预后。方法回顾性分析76例头颈部ACC肺转移患者的临床和随访资料。根据初始治疗分为手术、手术+放化疗、放化疗、支持治疗四组；根据国际肺转移分期系统（International Registry of Lung Metastases Staging System, IRLM）进行分期。采用Kaplan-Meier法、Log-rank检验比较不同治疗方式及不同IRLM分期患者的总生存期（overall survival, OS）及无进展生存期（progression-free survival, PFS）的统计学差异。结果接受手术治疗患者的OS及PFS优于支持性治疗或放疗/化疗的患者（OS: P < 0.000, 1; PFS: P < 0.000, 1）；IRLM低分期的OS和PFS优于高分期患者（OS: P < 0.000, 1; PFS: P < 0.000, 1）；单发肺转移、不合并胸腔积液患者具有更好的OS和PFS。结论接受手术治疗的ACC肺转移患者的远期预后与更好的OS和PFS相关。对于具备手术条件的ACC肺转移的患者，进行完整手术切除的意义高于其他治疗方案。

Bilateral kidney metastases from adenoid cystic carcinoma of lung: a case report and literature review

Adenoid cystic carcinoma (ACC) is a rare malignant tumor, usually arising from salivary glands and rarely found in other locations. ACC is characterized by asymptomatic course, slow growth pattern, perineural invasion and high incidence of late metastasis. Renal localization of metastasis is rare. Only 12 cases of renal metastasis were published and, to our best knowledge, no case of bilateral metastasis to the kidney has ever been reported. We present a case of a 58years old woman with bilateral renal metastasis from ACC of the right lung after fourteen years from lobectomy and radiotherapy for the primary presentation. The patient underwent bilateral robot-assisted partial nephrectomy in a two-stage approach. Despite its rare incidence and slow growth, ACC metastasis may simulate primary papillary renal carcinoma and occur many years after primary treatment. Therefore, lifelong follow-up, including abdominal imaging, is recommended.

Liver Resection for Metastasis of Adenoid Cystic Carcinoma of the Lacrymal Gland : A Case Report and Literature Review

Adenoid cystic carcinoma (ACC) is a rare malignant tumor. The first description of the ACC dates back to 1856 by Billroth. The ACC of the lacrimal glands are very rare. They are known for their locally aggressive character. Liver metastases are almost exceptional. We report the case of a patient with hepatic metastasis ACC. After eye enucleation of the primitive lacrimal gland ACC, the patient received external adjuvant radiotherapy. Three years later, she presented an upper abdominal pain. CT scan and MRI showed a liver tumor and the diagnosis of intrahepatic cholangiocarcinoma was made regarding imaging features. A left hepatectomy was performed; histology concluded to a liver metastasis of ACC. The immediate post-operative course was uneventful and no adjuvant treatment was decided. Thirty four months later, the patient presented with lung metastasis. Liver metastasis of ACC are very rare. Extended liver surgery is recommended especially for isolated liver metastasis with a long free gap between primary tumor and the liver metastasis. Keywords: Adenoid cystic carcinoma, Hepatic metastasis, Lacrymal gland

Possible local treatment for liver metastases of adenoid cystic carcinoma (ACC): single-centre experience and literature review.

BackgroundAdenoid cystic carcinoma (ACC) is a relatively indolent cancer, for which the major cause of death is distant metastases. The median survival time of patients with distant metastases of ACC is approximately 20 months. Although the liver is not the most common site of secondary ACC, effective treatment of liver metastases could improve patient survival. This study explored the clinical features and treatment of liver metastases of ACC in one centre and performed a literature review.MethodsThis is a retrospective cohort study. The records of 25 ACC patients with liver metastases in our hospital from January 2000 to September 2018 and 13 case reports (from 2000 to 2018) from PubMed published in English were reviewed together. Survival curves were estimated by the Kaplan-Meier method. Multivariate cox regression analysis was used to identify risk factors for overall survival (OS).ResultsPatients with liver metastases of ACC had a poor prognosis. The median survival time of patients with ACC liver metastases was 14 months (4–26 months), and the 1-, 2-, and 3-year survival rates were 55.8%, 28.5%, and 15.2%, respectively. Isolated liver metastases were more likely to benefit from local treatment, such as surgery and radiofrequency ablation (RFA), than multifocal metastases. The prognosis was worse for patients who received systemic treatment for multifocal liver metastases than for those who received other treatment. Synchronous liver metastases were the predictive factor for OS both in univariate and multivariate analysis.ConclusionsLocal treatment, such as surgical resection or RFA, may prolong the survival time of ACC patients with liver metastases. The definition of resectability for liver metastases needs further investigation.

GOLT1A-KISS1 fusion is associated with metastasis in adenoid cystic carcinomas

Genetic alterations can drive carcinogenesis. Numerous studies have shown that gene fusion is associated with cancer progression and could provide valuable biomarkers for clinical diagnosis or targets for cancer therapy. Adenoid cystic carcinoma (ACC) is a rare form of adenocarcinoma, characterized by frequent local recurrence and high rates of distant metastasis, ultimately resulting in low survival rates. Owing to the lack of effective therapeutic targets and limited biomarkers for diagnosis, a deeper understanding of the molecular basis of ACC is urgently needed. Here, we show that gene fusion is associated with ACC metastasis. We identified a metastasis suppressor KISS1 fused with a close-by gene, GOLT1A, in highly metastatic ACC cell lines and human specimens. Such fusion blocks KISS1 translation, but not transcription, by introducing 5’ upstream open reading frames (uORFs) in the GOLT1A-KISS1 fusion transcript. Deletion of these uORFs rescued KISS1 expression and reduced invasion and migration of metastatic ACC cells. We also detected GOLT1A-KISS1 fusion transcripts in other types of highly metastatic cancer cell lines. Taken together, our results highlight the significance of this novel GOLT1A-KISS1 gene fusion in tumor metastasis and provide a valuable biomarker for clinical diagnosis and future therapeutic targeting of ACC.

Roles of Proteoglycans in the Tumourigenesis and Development of Adenoid Cystic Carcinoma and Pleomorphic Adenoma of the Salivary Gland: A Systematic Review.

Salivary adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) are the most common types of salivary gland tumours; the former is malignant and the latter is benign but with features of a border tumour. Proteoglycans (PGs) produced by neoplastic myoepithelial cells are ubiquitous in both types of tumours. However, normal myoepithelial cells of salivary glands do not have the ability to secrete PGs. When the synthesis of PGs is blocked, the pulmonary metastasis and perineural growth of salivary ACC as well as the implanting growth of salivary PA are inhibited, highlighting the important functions of PGs in the tumourigenesis and development of these two tumours. In this review, we summarise literature from the past 40 years, including more recent findings from our laboratory, to clarify the pivotal roles of PGs produced by neoplastic myoepithelial cells in both the histogenesis and biological behaviours of ACC and PA.

Lung metastasis in adenoid cystic carcinoma of the head and neck.

Distant metastasis of adenoid cystic carcinoma (ACC) is most commonly identified in the lung, but risk factors are still on debate. Risk factors for lung metastasis were evaluated by using Cox proportional hazards model and Kaplan-Meier curves. Of 112 patients, 48% had distant metastasis; 94.4% of whom had lung metastasis. Univariable analysis revealed sublingual or minor salivary gland, tumor size ≥2.5 cm, and perineural invasion as risk factors (hazard ratio [HR]: 1.99 [1.02-3.91], 2.57 [1.19-5.58], and 2.46 [1.28-4.74], respectively), whereas size, perineural invasion, and local recurrence were risk factors in multivariable analysis (HR: 2.29 [1.05-4.96], 2.32 [1.09-4.96], and 2.68 [1.24-5.79], respectively). Sublingual gland or minor salivary glands ACC has a higher risk of lung metastasis. If the site is not considered, the following factors increased the risk of lung metastasis; (a) size ≥2.5 cm, (b) perineural invasion, and (c) local recurrence.

Tumor-derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF-NTRK1 pathway.

Salivary adenoid cystic carcinoma (SACC) is a rare head and neck malignancy characterized by unpredictable expansion, considerable perineural invasion and high risk of metastasis; however, the underlying mechanism of SACC progression remains unclear. Cancer-associated fibroblasts localized within the tumor microenvironment may promote cancer malignant transformation by enhancing tumor growth, blood vessel formation, inflammation development and metastasis occurrence. Small extracellular vesicles, including exosomes, are mediators of intercellular communication and can influence major tumor-associated pathways. The present study aimed to explore the exosome-mediated communication between SACC cells and fibroblasts. The results from confocal microscopy demonstrated that exosomes derived from the human cell line SACC-83 were internalized by the human periodontal ligament fibroblast (HPLF) cells. Following exosome internalization, HPLF cells appeared to enhance SACC-83 cell metastasis and were educated toward a protumorigenesis phenotype according to transcriptome RNA sequencing and reverse transcription-quantitative polymerase chain reaction analysis. This phenomenon included exosome-mediated stimulation of proinflammatory cytokines and nerve growth factor (NGF) secretion. Furthermore, NGF blockage reduced the enhanced SACC-83 cell invasion stimulated by the supernatant isolated from exosome-educated HPLF cells. In addition, the results reported that neurotrophic receptor tyrosine kinase 1 (NTRK1), which is the high-affinity NGF receptor, was significantly upregulated in human SACC-83 cells. These results demonstrated that SACC-83 cell-derived exosomes educated HPLF cells toward the protumorigenic phenotype via the NGF-NTRK1 pathway, which suggested that this type of exosomes may be used as a potential therapeutic target for SACC.

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma.

The incidence of recurrent t(6;9) translocation of the MYB proto-oncogene to NFIB (the gene that encodes nuclear factor 1 B-type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh-frozen SACC tissues and 41 fresh-frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial-mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin-1 (E-cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin-2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non-obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

PFKFB3促进腺样囊性癌ACC-2细胞增殖、迁移、侵袭和转移

Objective To evaluate the expression of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) in adenoid cystic carcinoma and the effects of PFKFB3 on the proliferation, migration, invasion and tumorigenesis in vivo of adenoid cystic carcinoma cells. Methods Immunohistochemistry and Western blotting were applied to detect the expression of PFKFB3 in 29 cases of adenoid cystic carcinoma tissues and 10 cases of para-carcinoma normal salivary gland tissues. PFKFB3 in adenoid cystic carcinoma ACC-2 cells was silenced by adenovirus vector. The effects of PFKFB3 silence on cell proliferation, migration, invasion and tumorigenesis in vivo and distant metastasis of adenoid cystic carcinoma cells were evaluated by cell proliferation assay, wound healing assay, Transwell assay, xenografted mice model and lung metastasis mice model. Results The results of immunohistochemical staining showed that the positive expression rate of PFKFB3 in adenoid cystic carcinoma tissues was 93.1% (27/29), and the positive expression rate of PFKFB3 in normal salivary gland tissues was 20.0% (2/10), with a significant difference (χ2=20.84, P<0.001). The results of methyl thiazolyl tetrazolium (MTT) assay showed that, compared with ACC-2 group, the proliferation activity of cancer cells with silence of PFKFB3 (PFKFB3--ACC-2) was significantly suppressed for 72 h (1.8±0.2 vs. 4.7±0.8, t=3.582, P=0.001). The results of wound healing assay showed that after scraping cells away for 24 h, the number of cells in the scratch area was 99.8±13.2 in the PFKFB3--ACC-2 group, which was significantly less than that in the ACC-2 group (263.0±97.4, t=2.868, P=0.029). Transwell results indicated that the number of cells passing through matrigel was 17.6±2.1 in the PFKFB3--ACC-2 group, which was less than that in the ACC-2 group (28.6±3.8, t=4.452, P=0.004). The tumor volume in the PFKFB3--ACC-2 [(623.5±134.1) mm3] was smaller than that in the ACC-2 group [(1 621.0±278.1) mm3,t=4.213, P=0.001]. More pulmonary metastases were found in the ACC-2 group than PFKFB3--ACC-2 group (18.1±3.2 vs. 4.1±2.2, t=6.322, P=0.001). Conclusion The expression of PFKFB3 is higher in adenoid cystic carcinoma tissue than normal salivary gland tissue, and the highly expressed PFKFB3 plays a driving role in the proliferation, migration, invasion and metastasis in adenoid cystic carcinoma. Key words: Carcinoma, adenoid cystic; Glycolysis; PFKFB3; Tumor development

Deregulation of Nicotinamide N-Methyltransferase and Gap Junction Protein Alpha-1 Causes Metastasis in Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (AdCC) is a malignant tumor that occurs in the salivary glands and frequently metastasizes. The aim of this study was to identify factors mediating AdCC metastasis. We established three AdCC cell lines by orthotropic transplantation and in vivo selection: parental, highly metastatic (ACCS-M-GFP), and lymph node metastatic (ACCS-LN-GFP) cells. We examined the three cell lines. DNA microarray indicated significantly altered processes in ACCS-LN-GFP cells: particularly, the expression of nicotinamide N-methyltransferase (NNMT) was enhanced the most. NNMT is associated with tumorigenesis and is a potential tumor biomarker. Concomitantly, we found-significant down-regulation of gap junction protein alpha-1. We suggest that ACCS-LN-GFP cells acquire cancer stem cell features involving the up-regulation of NNMT and the loss of gap junction protein alpha-1, leading to epithelial-mesenchymal transition and consequent AdCC metastasis. NNMT is a potential biomarker of AdCC.