lymphatic metastasis
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2022 ◽  
Vol 11 ◽  
Author(s):  
Chuqi Wang ◽  
Ming Chu

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.


Author(s):  
Dan Yu ◽  
Min Pan ◽  
Yanshi Li ◽  
Tao Lu ◽  
Zhihai Wang ◽  
...  

Abstract Background Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined. Methods The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC. Results We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability. Conclusions Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Matthew K. Siggins ◽  
Shiranee Sriskandan

Lymphatic vessels permeate tissues around the body, returning fluid from interstitial spaces back to the blood after passage through the lymph nodes, which are important sites for adaptive responses to all types of pathogens. Involvement of the lymphatics in the pathogenesis of bacterial infections is not well studied. Despite offering an obvious conduit for pathogen spread, the lymphatic system has long been regarded to bar the onward progression of most bacteria. There is little direct data on live virulent bacteria, instead understanding is largely inferred from studies investigating immune responses to viruses or antigens in lymph nodes. Recently, we have demonstrated that extracellular bacterial lymphatic metastasis of virulent strains of Streptococcus pyogenes drives systemic infection. Accordingly, it is timely to reconsider the role of lymph nodes as absolute barriers to bacterial dissemination in the lymphatics. Here, we summarise the routes and mechanisms by which an increasing variety of bacteria are acknowledged to transit through the lymphatic system, including those that do not necessarily require internalisation by host cells. We discuss the anatomy of the lymphatics and other factors that influence bacterial dissemination, as well as the consequences of underappreciated bacterial lymphatic metastasis on disease and immunity.


2021 ◽  
Author(s):  
Yapeng Wang ◽  
Xiaoyu Niu ◽  
Lihui Wang ◽  
Yunlong Li ◽  
Baoping Qiao

Abstract Purpose To evaluate clinicopathologic features and survival outcomes of unilocular cystic renal cell carcinoma (cRCC) compared with purely solid renal cell carcinoma (RCC), and to evaluate the oncologic aggressiveness of unilocular cRCC. Methods The relevant data of 957 patients with sporadic unilateral RCCs underwent surgical treatment in 2 institutions from Jan 2014 to Oct 2018 were obtained. We excluded multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), RCCs with multilocular cysts and necrotic RCCs. 74 unilocular cRCCs were identified by pathology reports. We performed propensity score matching (PSM) and randomly selected 148 purely solid RCCs. The clinicopathologic features and survival outcomes were compared properly. Results After PSM, age, BMI, Charlson Comorbidity Index, and postoperative Chronic Kidney Disease grade were not significantly different. Both overall survival and cancer-specific survival of unilocular cRCCs were significantly better than the purely solid RCCs by the log-rank test. Twenty-five cases of solid RCCs were in the pT3 or pT4 stage, while no pT3 or pT4 tumors were found in unilocular cRCCs. Fuhrman grade, pT stage, lymphatic metastasis and tumor diameter were found to be independent prognostic factors. Conclusion Unilocular cRCCs have a lower Fuhrman grade and pathological stage and a better prognosis compared with solid RCC. Unilocular cRCCs still probably have lymphatic metastasis at diagnosis and may have postoperative metastasis, which is different from MCRNLMP. We recommend that the diagnosis of unilocular cRCC should be reflected in pathology reports. Different subtypes of cRCC should be taken into consideration in counseling and management.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaolong Tang ◽  
Yahang Liang ◽  
Guorui Sun ◽  
Qingsi He ◽  
Hui Qu ◽  
...  

AbstractUbiquilin 4 (UBQLN4) is an important member of the ubiquitin-like protein family. An increasing number of studies have shown that UBQLN4 is an important regulator of tumorigenesis. Nevertheless, the biological function and detailed mechanisms of UBQLN4 in colorectal cancer (CRC) development and progression remain unclear. Here, we identified UBQLN4 upregulation in CRC tissues and it is positively associated with CRC size, TNM stage, and lymphatic metastasis. Patients with high UBQLN4 expression had a poor prognosis. Functionally, overexpression of UBQLN4 significantly promoted CRC cell proliferation, migration, and invasion, while UBQLN4 silencing elicited the opposite effect. This result was consistent with the conclusion that UBQLN4 expression correlated positively with the CRC size and lymphatic metastasis. In vivo, UBQLN4 silencing also inhibited tumor growth. Mechanistically, using gene set enrichment analysis (GSEA) and western blot experiments, we identified that UBQLN4 activated the Wnt/β-catenin signaling pathway to upregulate β-catenin and c-Myc expression, thereby promoting CRC proliferation, migration and invasion. A rescue experiment further verified this conclusion. Dual luciferase reporter, real-time quantitative PCR (RT-qPCR), western blot and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) directly bound to the UBQLN4 core promoter region and activated its transcription, upregulating β-catenin and c-Myc expression to promote CRC progression. Thus, our findings suggest that UBQLN4 is a key oncogene in CRC and may be a promising target for the diagnosis and treatment of patients with CRC.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Meng Wang ◽  
Yue Li ◽  
Yunyun Xiao ◽  
Muwen Yang ◽  
Jinxin Chen ◽  
...  

AbstractNicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer’s poor prognosis; however, nicotine’s role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6044
Author(s):  
Kyungmin Ji ◽  
Zhiguo Zhao ◽  
Mansoureh Sameni ◽  
Kamiar Moin ◽  
Yong Xu ◽  
...  

Breast cancer frequently metastasizes to lymphatics and the presence of breast cancer cells in regional lymph nodes is an important prognostic factor. Delineating the mechanisms by which breast cancer cells disseminate and spatiotemporal aspects of interactions between breast cancer cells and lymphatics is needed to design new therapies to prevent lymphatic metastases. As triple-negative breast cancer (TNBC) has a high incidence of lymphatic metastasis, we used a three-dimensional (3D) coculture model of human TNBC cells and human microvascular lymphatic endothelial cells (LECs) to analyze TNBC:LEC interactions. Non-invasive analyses such as live-cell imaging in real-time and collection of conditioned media for secretomic analysis were facilitated by our novel microfluidic chambers. The volumes of 3D structures formed in TNBC:LEC cocultures are greater than that of 3D structures formed by either LEC or TNBC monocultures. Over 4 days of culture there is an increase in multicellular invasive outgrowths from TNBC spheroids and an association of TNBC spheroids with LEC networks. The increase in invasive phenotype also occurred when TNBC spheroids were cultured in LEC-conditioned media and in wells linked to ones containing LEC networks. Our results suggest that modeling spatiotemporal interactions between TNBC and LECs may reveal paracrine signaling that could be targeted to reduce lymphatic metastasis.


2021 ◽  
Author(s):  
Dan Yu ◽  
Min Pan ◽  
Yanshi Li ◽  
Tao Lu ◽  
Zhihai Wang ◽  
...  

Abstract Background: Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined. Methods: The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, and luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC. Results: We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability. Conclusions: Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.


2021 ◽  
Author(s):  
Ying Kong ◽  
Kai Wang ◽  
Ai-li Suo

Abstract Background: Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis, but the aetiology is poorly understood. Long standing gallstone and chronic inflammation had been observed to be risk factors for GBC. Gallstone and chronic infection may lead to increased turnover of primary bile acids to secondary bile acids and inflammatory cytokines, which were known tumor promoters and might be responsible for GBC. But the exact molecular mechanism was not fully understood. Results: Our results showed that gallstones and chronic infection could increase the levels of inflammatory cytokines, and promoted the expression of CACUL1 and ITGBL1. Our study furtherly identified the highly expressed patients of CACUL1 and ITGBL1 had a poor prognosis, and them therefore might serve as a potential prognostic biomarker for GBC patients. CACUL1 promoted the expression of ITGBL1 through NRF2. Furthermore, ITGBL1 promoted the migration and invasion of GBC cells. In addition, ITGBL1 was found to induce lymphangiogenesis through the ITGA9/VEGF-C pathway and promote lymphatic metastasis. Conclusions: Our study provided new insight into GBC pathogenesis that chronic bacterial infection and gallstones leading to the production of carcinogenic precursors and inflammatory cytokines promote lymphangiogenesis and lymph node metastasis of cancer cells through CACUL1/NRF2/ITGBL1/ ITGA9/VEGF-C pathway.


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