Lymphatic vessel: origin, heterogeneity, biological functions, and therapeutic targets.

Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role in maintaining homeostasis among various tissues and organs. They are tasked with a serious of responsibilities, including the regulation of lymph absorption and transport, the orchestration of immune surveillance and responses. Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks. Lymphangiogenesis, as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins, is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo. However, abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases. Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis, to further modulate the progression of diseases. Actually, an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation. Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis, but improves the efficacy of diverse treatments. In conclusion, we present a comprehensive overview of lymphatic vessel development and physiological functions, and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases. Moreover, we summarize the targeting therapeutic values of abnormal lymphangiogenesis, providing novel perspectives for treatment strategy of multiple human diseases.

CRIP1 Reshapes the Gastric Cancer Microenvironment to Facilitate Development of Lymphatic Metastasis.

Lymphangiogenesis in tumors provides an auxiliary route for cancer cell invasion to drainage lymph nodes, facilitating the development of lymphatic metastasis (LM). However, the mechanisms governing tumor lymphangiogenesis and lymphatic permeability in gastric cancer (GC) remain largely unknown. Here, the unprecedented role and mechanism of cysteine-rich intestinal protein-1 (CRIP1) in mediating the development of GC LM is uncovered. A series of assays are performed to identify downstream targets of CRIP1, and rescue experiments are performed to confirm the effects of this regulatory axis on LM. CRIP1 overexpression facilitates LM in GC by promoting lymphangiogenesis and lymphatic vessel permeability. CRIP1 promotes phosphorylation of cAMP responsive element binding protein 1(CREB1), which then mediates vascular endothelial growth factor C (VEGFC) expression necessary for CRIP1-induced lymphangiogenesis and transcriptionally promotes C-C motif chemokine ligand 5 (CCL5) expression. CCL5 recruits macrophages to promote tumor necrosis factor alpha (TNF-α) secretion, eventually enhancing lymphatic permeability. The study highlights CRIP1 regulates the tumor microenvironment to promote lymphangiogenesis and LM in GC. Considering the current limited understanding of LM development in GC, these pathways provide potential targets for future therapeutics.

The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Recently, there have been several randomized clinical trials (RCTs) conducted to evaluate the efficacy and safety of metformin plus standard treatment in inoperable cancer patients. Our meta-analysis aimed to assess the efficacy of metformin in combination with standard treatment in inoperable cancer patients. METHODS: PubMed and Embase databases were systematically searched for relevant RCTs investigating the efficacy of adding metformin to standard treatment for cancer patients. The pooled relative risk (RR) for tumor response and safety was calculated to assess the efficacy of combining metformin with standard treatment. Meta-analysis was subsequently performed to pool the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). RESULTS: Ten RCTs comprising 1033 patients were included in our current meta-analysis. In patients with breast cancer, results of meta-analysis showed that the addition of metformin to standard treatment was beneficial to objective response rate (ORR) with 30.3% (33/109) in the metformin plus standard treatment group and 16.1% (18/112) in the placebo group (RR 1.92, 95% CI: 1.19-3.10, P=0.008). OS and PFS were not significantly improved in patients who received metformin plus standard treatment compared with those who received placebo plus standard treatment (OS: HR 1.02, 95% CI: 0.71-1.46, P=0.916; PFS: HR 1.14, 95% CI: 0.86-1.50, P=0.366). For lung cancer patients, meta-analysis results showed adding metformin to standard treatment could benefit ORR (metformin 65.3% vs. placebo 54.6%, RR 1.22, 95% CI: 1.03-1.43, P=0.018) with no significant survival benefit in the metformin group. For patients with pancreatic cancer, the pooled ORR was 17.6% (16/91) in metformin plus standard treatment group and 20% (18/90) in the placebo group, indicating metformin did not benefit ORR (RR 0.85, 95% CI: 0.49-1.49, P=0.576). Besides, the addition of metformin to standard treatment did not increase the incidence rate of adverse effects. CONCLUSIONS: Our results indicated that addition of metformin to standard treatment was beneficial to ORR in inoperable breast or lung cancer patients without increasing the incidence of adverse effects. However, adding metformin to standard treatment could not benefit OS and PFS.

A 3'-tRNA-derived fragment enhances cell proliferation, migration and invasion in gastric cancer by targeting FBXO47.

Increasing evidence demonstrates that tRNA-derived fragments (tRFs) exert important effects and are dysregulated in various human cancer types. However, their roles in gastric cancer (GC) remain unknown. Here we identified the functional effects of tRF-3019a (derived from tRNA-Ala-AGC-1-1) in GC. We demonstrated that tRF-3019a was upregulated in GC tissues and cell lines. Phenotypic studies revealed that tRF-3019a overexpression enhances GC cell proliferation, migration and invasion. Conversely, tRF-3019a knockdown inhibits GC cell malignant activities. Mechanistic investigation implies that tRF-3019a directly regulates tumor suppressor gene FBXO47. Furthermore, tRF-3019a levels may discriminate GC tissues from nontumorous tissues. Taken together, our results reveal that tRF-3019a modulates GC cell proliferation, migration and invasion by targeting FBXO47, and it may serve as a potential diagnostic biomarker for GC.

The tRNA-Derived Fragment-3017A Promotes Metastasis by Inhibiting NELL2 in Human Gastric Cancer.

tRNA-derived fragments (tRFs) are a new classification of small non-coding RNAs (sncRNAs) derived from the specific cleavage of precursors and mature tRNAs. Accumulating recent evidence has shown that tRFs are frequently abnormal in several cancers. Nevertheless, the role of tRFs in gastric cancer and its mechanism remain unclear. In this study, we found abnormal expression of tRF-3017A (derived from tRNA-Val-TAC) in gastric cancer tissues and cell lines and confirmed its effect on promoting the invasion and migration of gastric cancer cells through functional experiments in vitro. Analysis of clinicopathologic data showed patients with higher tRF-3017A were associated with significantly higher lymph node metastasis. Mechanistic investigation implies that tRF-3017A regulates the tumor suppressor gene NELL2 through forming the RNA-induced silencing complex (RISC) with Argonaute (AGO) proteins. In this study, we found that higher tRF-3017A were associated with significantly higher lymph node metastasis in gastric cancer patients and the tRF-3017A may play a role in promoting the migration and invasion of gastric cancer cells by silencing tumor suppressor NELL2.