• Angiogenesis
• Mast cells
• Metastasis
• Tumor progression

• agonism
• immune cells
• immunotherapy
• protease-activated receptors (PARs)
• proteases

• Peptide Hydrolases/metabolism
• Receptors, G-Protein-Coupled
• Receptors, Proteinase-Activated/agonists
• Receptors, Proteinase-Activated/metabolism
• Signal Transduction
• Immunotherapy
• Neoplasms/immunology
• Neoplasms/therapy
• Immune System Diseases/immunology
• Immune System Diseases/therapy
• Humans
• Animals

• ABCA1
• Bioinformatics
• Biomarker
• Gastric adenocarcinoma
• Tumor-Associated macrophages

• BCF-XD-ZL-20220118-032 the Bethune Tumour Clinical Research Program
• 2018ZB064, 2021ZB127 Traditional Chinese Medicine Science and Technology Program of Zhejiang Province
• 2A12012014 the Pang Dexiang Famous Old Chinese Medicine Experts Inheritance Studio

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In terms of the advanced stages, systemic treatments have allowed patients to achieve clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies have been developed and clinically evaluated with interesting results. However, on the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

• cancer therapy
• hepatocellular carcinoma
• immune checkpoint inhibitors
• immunotherapy
• targeted therapy
• tyrosine kinase inhibitors

While bone metastasis is not common in gastric adenocarcinoma (GaC), it can have important impacts on prognosis. This large cohort study aimed at exploring factors associated with bone metastasis in GaC and investigating the time-dependent cumulative mortalities and prognostic factors in GaC patients with bone metastasis at the population level.

Data on patients with GaC diagnosed in 2010–2016 were retrieved from a large population-based database. We explored factors associated with bone metastasis using the multivariable-adjusted logistic model. We then calculated the time-dependent cancer-specific mortalities in GaC patients with bone metastasis using the cumulative incidence function and compared mortalities across subgroups using Gray’s test. We further assessed factors associated with mortality using the multivariable-adjusted Fine–Gray subdistribution hazard model.

Together 11,072 eligible patients with metastatic GaC were enrolled, which comprised 1,511 (14%) people with bone metastasis and 9,561 (86%) with other metastasis, encompassing 6,999 person-years of follow-up. Bone metastasis was more frequently detected in 2014 or later, in younger patients, in patients with gastric cardia cancers, in people with signet-ring cell carcinoma, and in those with poorly differentiated/undifferentiated cancers; it was less commonly observed in black patients. Bone metastasis was associated with more frequent brain and lung metastases. The median survival of patients with bone metastasis was 4 months; the 6-month and 3-year cancer-specific cumulative mortalities were 56% and 85%, respectively. In patients receiving chemotherapy, American Indians/Alaskan Natives, patients with gastric antrum/pylorus cancers, and those with positive lymph nodes had higher mortality risks, while those undergoing resection had lower mortality hazards.

In GaC patients, bone metastasis was associated with various clinicopathologic factors including age, ethnicity, tumor location, histology, differentiation, and metastasis to other sites. Patients with bone metastasis had poor prognosis which was associated with ethnicity, tumor location, lymph node involvement, and treatment. Our findings provide important hints for tailed patient management and for further mechanistic investigations.

• Fine–Gray subdistribution hazard regression
• bone metastasis
• competing risk analysis
• cumulative incidence function
• gastric adenocarcinoma
• large population-based cohort study
• long-term survival

Gastric cancer is among the most common malignant tumors at home and abroad, because its early symptoms are mostly insidious, which leads to distant metastasis when gastric cancer is first diagnosed. The common metastatic sites of gastric cancer are mainly the liver, lung, and peritoneum, but bone metastasis is relatively rare, and the prognosis of gastric cancer bone metastasis is very poor. Therefore, this study is built on the SEER database to analyze the related risk factors of gastric cancer bone metastasis and related factors affecting the prognosis of gastric cancer patients, aiming at improving clinicians' understanding of clinical diagnosis and prognosis of bone metastasis of gastric cancer, thus reducing misdiagnosis and missed diagnosis.

The SEER database was collected to screen out patients with gastric cancer bone metastases and nonbone metastases matched with them from 2010 to 2016, and the Kaplan-Meier method was used to draw survival curves, and the comparison between survival curves was performed by Log-rank test to analyze the overall survival of the two groups of patient's time. Logistic regression analysis was used to analyze the related risk factors of gastric cancer bone metastasis, and the Cox regression proportional hazard model was used to analyze the relationship between gastric cancer bone metastasis and patient prognosis.

Using Kaplan-Meier survival curve to analyze the 1, 3, and 5-year survival rates of gastric cancer patients with bone metastasis and non-metastasis groups were 14.2%, 1.8%, 0.6% and 71.4%, 44.3%, 36.4%, respectively; the average survival rate of the metastatic group was The time was 4.0 months (95%CI: 3.475~4.525), and the average survival time of the non-metastatic group was 30.0 months (95%CI: 26.778~33.222). The difference between the two groups was statistically significant (χ² = 1076.866, P < 0.001). Multivariate logistic regression analysis showed that race (P = 0.007, OR = 1.296), grade (P < 0.001, OR = 0.575), marital status (P < 0.001, OR = 0.040), tumor size (P = 0.006, OR = 0.752), TNM stage (P < 0.001), T stage (P = 0.023, OR = 0.882), and M stage (P < 0.001, OR = 44.958) are independent risk factors for gastric cancer bone metastasis. The Cox univariate analysis suggests that gastric cancer bone metastasis is a risk factor for the prognosis of gastric cancer patients. The Cox multivariate analysis validates that gastric cancer bone metastasis (HR = 0.584, 95% CI: 0.497~0.688, P < 0.001) is independent of the overall survival rate of gastric cancer patients.

Race, grade, marital status, tumor size, TNM stage, T stage, and M stage are independent risk factors for gastric cancer bone metastasis; and gastric cancer bone metastasis is an independent risk factor that affects the prognosis of gastric cancer patients. Therefore, for such high-risk groups, large range screening of the above indicators can effectively improve the prognosis of gastric cancer patients to a certain extent.

• Bone
• Immunity
• Metastasis
• Myeloid

Background: Mast cells (MCs) contain proangiogenic factors, in particular tryptase, associated with increased angiogenesis in several tumours. With special reference to pancreatic cancer, few data have been published on the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue (PDAT) and adjacent normal tissue (ANT). In this study, density of mast cells positive for c-Kit receptor (MCDP-c-KitR), density of mast cells positive for tryptase (MCDPT), area of mast cells positive for tryptase (MCAPT), and angiogenesis in terms of microvascular density (MVD) and endothelial area (EA) were evaluated in a total of 45 PDAT patients with stage T_2–3N_0–1M₀. Results: For each analysed tissue parameter, the mean ± standard deviation was evaluated in both PDAT and ANT and differences were evaluated by Student’s t-test (p ranged from 0.001 to 0.005). Each analysed tissue parameter was then correlated to each other one by Pearson t-test analysis (p ranged from 0.01 to 0.03). No other correlation among MCDP-c-KitR, MCDPT, MCAPT, MVD, EA and the main clinical–pathological characteristics was found. Conclusions: Our results suggest that tissue parameters increased from ANT to PDAT and that mast cells are strongly associated with angiogenesis in PDAT. On this basis, the inhibition of MCs through tyrosine kinase inhibitors, such as masitinib, or inhibition of tryptase by gabexate mesylate may become potential novel antiangiogenetic approaches in pancreatic cancer therapy.

• adjacent normal tissue
• angiogenesis
• c-Kit receptor
• endothelial area
• mast cells
• microvascular density
• pancreatic cancer tissue
• tryptase

• prostate adenocarcinoma
• connectivity map database
• bioinformatics

• Adult
• Collagen Type I, alpha 1 Chain
• Computational Biology/methods
• Databases, Genetic
• Drug Compounding/methods
• Gabexate/therapeutic use
• Gene Expression Profiling/methods
• Humans
• Kaplan-Meier Estimate
• Male
• Piperazines/therapeutic use
• Prostate/pathology
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/physiopathology
• Tolnaftate/therapeutic use

• angiogenesis
• cancer
• gastric cancer
• immune cells
• inflammation
• lymphangiogenesis
• mast cells

• Animals
• Biomarkers
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphangiogenesis/genetics
• Lymphangiogenesis/immunology
• Mast Cells/immunology
• Mast Cells/metabolism
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Signal Transduction
• Stomach Neoplasms/etiology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

• No grant number available Regione Campania CISI-Lab Project
• No grant number available CRèME Project and TIMING Project

• bone marrow microenvironment
• cancer-induced bone pain
• macrophages
• mast cells
• osteoblasts
• osteoclasts
• stromal cells

• UL1 TR001420 NCATS NIH HHS

C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients. It has been found a strong correlation between MVD and MCDPT, and MCs-c-KitR, MVD and MCs density positive to tryptase (MCDPT), and MCs-c-KitR and MCDPT by Pearson correlation. These data suggest an involvement of both MCDPT and MCs-c-KitR in BC tumor angiogenesis. Furthermore, BC tissue expressing c-KitR could be a putative predictive factor to c-KitR-TK inhibitors. In this way, selected patients with higher MCs-c-KitR could be candidate to receive c-KitR-TK inhibitors (e.g. masitinib, sunitinib) or tryptase inhibitors (e.g. nafamostat mesilate, gabexate mesilate).

• C-Kit receptor
• angiogenesis
• breast cancer
• mast cells
• tryptase

Literature data suggest that inflammatory cells such as mast cells (MCs) are involved in angiogenesis. MCs can stimulate angiogenesis by releasing of well identified pro-angiogenic cytokines stored in their cytoplasm. In particular, MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor. Nevertheless, few data are available concerning the role of MCs positive to tryptase in primary pancreatic cancer angiogenesis. This study analyzed the correlation between mast cells positive to c-Kit receptor (c-Kit⁺ MCs), the density of MCs expressing tryptase (MCD-T) and microvascular density (MVD) in primary tumor tissue from patients affected by pancreatic ductal adenocarcinoma (PDAC). A series of 35 PDAC patients with stage T_2-3N_0-1M₀ (by AJCC for Pancreas Cancer Staging 7^th Edition) were selected and then undergone to surgery. Tumor tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of number of c-Kit⁺ MCs, MCD-T and MVD. The above parameters were related each other and with the most important main clinico-pathological features. A significant correlation between c-Kit⁺ MCs, MCD-T and MVD groups each other was found by Pearson t-test analysis (r ranged from 0.75 to 0.87; p-value ranged from 0.01 to 0.04). No other significant correlation was found. Our in vivo preliminary data, suggest that tumor microenvironmental MCs evaluated in terms of c-Kit⁺ MCs and MCD-T may play a role in PDAC angiogenesis and they could be further evaluated as a novel tumor biomarker and as a target of anti-angiogenic therapy.

• angiogenesis
• c-Kit-receptor
• mast cells
• pancreatic ductal adenocarcinoma
• tryptase

To explore expression of angiopoietin-like protein 2 (ANGPTL2) and its effect on biological behavior such as proliferation and invasiveness in gastric cancer.

Western blotting was used to detect expression of ANGPTL2 in 60 human normal gastric tissues, 60 human gastric cancer tissues and gastric cell lines including GES-1, N87, SGC7901, BGC823 and PAMC82. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assay were used to detect the proliferation and invasive ability of gastric cancer cells.

Compared to normal tissues, ANGPTL2 protein levels were significantly upregulated in gastric tissues, and this level was closely correlated with gastric tumor grade, clinical stage and lymph node metastasis. Compared to GES-1 cells, ANGPTL2 mRNA and protein levels were significantly increased in gastric cancer cells including N87, SGC7901, BGC823 and PAMC82. The expression of ANGPTL2 in highly malignant gastric cancer cell lines BGC823 and PAMC82 was significantly higher than in low malignancy gastric cancer cell lines N87 and SGC7901. MTT and Transwell experiments indicated that the proliferation rate and invasive ability of stable overexpressed gastric cancer cells was faster than in cells transfected with Lv-NC and blank control cells, and the invasive ability of stable overexpressed gastric cancer cells was higher than that of cells transfected with Lv-NC and blank control cells.

ANGPTL2 contributed to proliferation and invasion of gastric cancer cells. In clinical treatment, ANGPTL2 may become a new target for treatment of gastric cancer.

• Gastric cancer
• Angiopoietin-like protein 2
• Cell invasion
• Cell proliferation

• Adult
• Aged
• Aged, 80 and over
• Angiopoietin-Like Protein 2
• Angiopoietin-like Proteins
• Angiopoietins/genetics
• Angiopoietins/metabolism
• Cell Differentiation
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Female
• Humans
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Invasiveness
• Neoplasm Staging
• RNA Interference
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transfection
• Up-Regulation

• Anti-cancer therapy
• Mast cells
• New targets