Mast Cells Positive for c-Kit Receptor and Tryptase Correlate with Angiogenesis in Cancerous and Adjacent Normal Pancreatic Tissue.

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 T2-3N0-1M0. 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.

Microvascular Density, Endothelial Area, and Ki-67 Proliferative Index Correlate Each Other in Cat Post-Injection Fibrosarcoma.

Soft tissue sarcomas are a large group of different tumor types both in humans and in animals. Among them, fibrosarcoma is the most frequent malignant mesenchymal tumoral form in cats, representing up to 28% of all cat skin tumors, while human fibrosarcoma, fortunately, only represents 5% of all sarcomas and 0.025% of the world-wide burden of tumors. This low incidence in humans leads to consideration of this group of tumoral diseases as rare, so therapeutic options are few due to the difficulty of starting clinical trials. In this context, the identification of research models for fibrosarcomas could be of great interest to deepen knowledge in this field and recognize new or possible biological pathways involved in tumor progression and metastasis. Angiogenesis is considered a fundamental scattering cause of tumor aggressiveness and progression in all forms of cancer, but only a few research parameters were developed and reported to express them quantitatively and qualitatively. The role in angiogenesis of microenvironmental stromal cells, such as fibroblasts, lymphocytes, mast cells, and macrophages, was largely demonstrated since this topic was first approached, while quantification of new vessels and their blood capacity in tumoral area is a relatively recent approach that could be well developed thanks to expertise in immunohistochemistry and image analysis. In this paper, a crossing study evaluating microvascular density (MVD), endothelial area (EA), and Ki-67 proliferative index was reported for a series of formalin-fixed and paraffin-embedded tissue samples from 99 cat patients, affected by cat post-injection fibrosarcoma, by using a till ×400 magnification light microscopy. We aim to demonstrate that cat pets may be considered a useful animal model for better studying the correspondent human diseases and we report, for the first time to our knowledge, experimental data in terms of correlation among MVD, EA, and Ki-67 strictly involved in aggressiveness and tumoral progression.

Histological features of Rickettsia-like organisms in the European flat oyster (Ostrea edulis L.).

The European flat oyster (Ostrea edulis L.) represents an economically important oyster production in Southern Italy, widespread in natural beds along the coast. The practice to be eaten raw is an everlasting concern for possible health risk with a need to stringently monitor the health of aquatic environment. A screening survey using histopathological examination was undertaken by harvesting O. edulis from different sites along the Apulian coast of Italy. Tissue samples of the digestive gland, kidney, gonad, and gill were provided for morphologic study in light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) analysis. The LM observations revealed spherical cytoplasmic inclusions as basophilic prokaryote colonies in 13/250 oysters. The TEM and SEM confirmed the presence of intracytoplasmic inclusions of Rickettsia-like organisms (RLOs), merely in the epithelial cells of the digestive gland tubule tissues in the 13 oysters. Within intracytoplasmic vacuoles, RLOs exhibited a prokaryotic characteristic ultrastructure with transverse binary fission, a DNA zone full of chromatin fibers and a granular periplasmic ribosome zone. O. edulis were found positive for RLOs in wild oysters from Manfredonia, while the other sites were found free of pathological inclusions. Thus, we present the first report of a Rickettsia-like infection in the Apulian wild oyster (O. edulis) from Italy, including an ultrastructural description and pathological characterization.

Thymidine Phosphorylase Expression and Microvascular Density Correlation Analysis in Canine Mammary Tumor: Possible Prognostic Factor in Breast Cancer.

Purpose: The thymidine phosphorylase (TP) is a key enzyme involved in the metabolism of pyrimidines. Inhibition or downregulation of this enzyme causes accumulation of metabolites with consequences in DNA replication. TP regulates angiogenesis and chemotactic activity of endothelial cells. Different studies showed the presence of TP upregulation in human cancer but the correlation between TP expression and the microvascular density (MVD) in canine mammary tumors is unknown. The aim of this study was to investigate a possible correlation between the MVD and TP expression in tumor cells of canine mammary tumors of different degree of severity (G1-G3) by immunohistochemical analysis. Methods: Sixty-eight samples of spontaneous mammary neoplasia of 5-12 cm in diameter were collected from purebred and mixed-breed dogs (mean aged = 9.5 ± 7), not subject to chemotherapy treatments in veterinary clinics. Histopathological analysis and immunostaining were performed. Results: Carcinoma simple samples have been classified as 72.06% of tubule-papillary, 20.59% cysto-papillary, and 7.35% tubular carcinomas. Immunostainings revealed a marked cytoplasmic expression of TP in 30.88% of samples, mild in 32.35%, weaker in 22.07%, and negative in 14.70%. The correlation analysis and two-way ANOVA showed a linear correlation between MVD and TP with a coefficient of correlation (r) > 0.5 (p < 0.05) in G2 and G3. No correlation between variables was found in G1. Conclusions: These findings suggest that cytoplasmic TP overexpression is correlated with microvascular density in canine mammary tumors, in severe grade, and it can be a potential prognostic factor in breast cancer.

Tumor-Associated Macrophages and Mast Cells Positive to Tryptase Are Correlated with Angiogenesis in Surgically-Treated Gastric Cancer Patients.

Mast cells and macrophages can play a role in tumor angiogenesis by stimulating microvascular density (MVD). The density of mast cells positive to tryptase (MCDPT), tumor-associated macrophages (TAMs), and MVD were evaluated in a series of 86 gastric cancer (GC) tissue samples from patients who had undergone potential curative surgery. MCDPT, TAMs, and MVD were assessed in tumor tissue (TT) and in adjacent normal tissue (ANT) by immunohistochemistry and image analysis. Each of the above parameters was correlated with the others and, in particular for TT, with important clinico-pathological features. In TT, a significant correlation between MCDPT, TAMs, and MVD was found by Pearson t-test analysis (p ranged from 0.01 to 0.02). No correlation to the clinico-pathological features was found. A significant difference in terms of mean MCDPT, TAMs, and MVD between TT and ANT was found (p ranged from 0.001 to 0.002). Obtained data suggest MCDPT, TAMs, and MVD increased from ANT to TT. Interestingly, MCDPT and TAMs are linked in the tumor microenvironment and they play a role in GC angiogenesis in a synergistic manner. The assessment of the combination of MCDPT and TAMs could represent a surrogate marker of angiogenesis and could be evaluated as a target of novel anti-angiogenic therapies in GC patients.

C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients.

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).

The density of mast cells c-Kit+ and tryptase+ correlates with each other and with angiogenesis in pancreatic cancer patients.

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 T2-3N0-1M0 (by AJCC for Pancreas Cancer Staging 7th 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.

Tryptase mast cell density, protease-activated receptor-2 microvascular density, and classical microvascular density evaluation in gastric cancer patients undergoing surgery: possible translational relevance.

BACKGROUND: Mast cells (MCs) can stimulate angiogenesis, releasing several proangiogenic cytokines stored in their cytoplasm. In particular, MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor via protease-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. Nevertheless, no data are available concerning the relationship among tryptase MC density (TMCD), endothelial cells (ECs) positive to PAR-2 microvascular density (PAR-2-MVD) and classical MVD (C-MVD) in gastric cancer (GC) angiogenesis. METHODS: In this study, we analyzed the correlation of TMCD, PAR-2-MVD, C-MVD with each other and with the main clinicopathological features in GC patients who underwent surgery. A series of 77 GC patients with stage T2-3N2-3M0 (classified by the American Joint Committee on Cancer for Gastric Cancer, 7th edition) were selected and then underwent surgery. RESULTS: Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of numbers of TMCD, PAR-2-MVD and C-MVD. A significant correlation between the TMCD, PAR-2-MVD and C-MVD groups with each other was found by Pearson t-test analysis (r ranged from 0.64 to 0.76; p value ranged from 0.02 to 0.03). There was no other significant correlation between the above parameters and clinicopathological features. CONCLUSIONS: Our in vivo preliminary data suggest that TMCD and PAR-2-MVD may play a role in GC angiogenesis and they could be further evaluated as a target of antiangiogenic therapy.

First report of Angiostrongylus vasorum in a wild red fox (Vulpes vulpes) from Apulia (Italy).

Severe lung strongylosis was detected in a wild red fox (Vulpes vulpes) (1/12) from Apulia (Italy). We performed routine diagnostics on 12 foxes found dead in Apulia. Eleven of them showed lesions consistent with a vehicle collision. However, the remaining fox appeared to have died from other causes. At necropsy we observed, catarrhal enteritis, fatty liver, lung congestion with some areas rm in consistence and brain haemorrhages and malacia. Histopathology revealed lung brosis with mononucleate cells in ltration, thrombosis a several larval nematodes spread in the parenchyma, interstitial nephritis, interstitial myocarditis, encephalitis, encephalomalacia, and a brain granuloma. The larvae recovered from the lung parenchyma were identi ed as the rst stage larvae of Angiostrongylus vasorum. This is the rst documented report of angiostrongylosis in a fox in Southern Italy.

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery.

Mast Cells (MCs) play a role in immune responses and more recently MCs have been involved in tumoral angiogenesis. In particular MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. MCs can release tryptase following c-Kit receptor activation. Nevertheless, no data are available concerning the relationship among MCs Density Positive to Tryptase (MCDPT) and Microvascular Density (MVD) in both primary gastric cancer tissue and loco-regional lymph node metastases. A series of 75 GC patients with stage T2-3N2-3M0 (by AJCC for Gastric Cancer Seventh Edition) undergone to radical surgery were selected for the study. MCDPT and MVD were evaluated by immunohistochemistry and by image analysis system and results were correlated each to other in primary tumor tissue and in metastatic lymph nodes harvested. Furthermore, tissue parameters were correlated with important clinico-pathological features. A significant correlation between MCDPT and MVD was found in primary gastric cancer tissue and lymph node metastases. Pearson t-test analysis (r ranged from 0.74 to 0.79; p-value ranged from 0.001 to 0.003). These preliminary data suggest that MCDPT play a role in angiogenesis in both primary tumor and in lymph node metastases from GC. We suggest that MCs and tryptase could be further evaluated as novel targets for anti-angiogenic therapies.

Mast cells positive to tryptase, endothelial cells positive to protease-activated receptor-2, and microvascular density correlate among themselves in hepatocellular carcinoma patients who have undergone surgery.

BACKGROUND: Mast cells (MCs) can stimulate angiogenesis, releasing several proangiogenic cytokines stored in their cytoplasm. In particular MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase phosphorylation. Nevertheless, no data are available concerning the relationship between MC density positive to tryptase (MCDPT), endothelial cells positive to PAR-2 forming microvascular density (PAR-2-MVD), and classical MVD (C-MVD) in hepatocellular carcinoma (HCC) angiogenesis. This study analyzed the correlation between MCDPT, PAR-2-MVD, and C-MVD, each correlated to the others and to the main clinicopathological features, in early HCC patients who underwent surgery. METHODS: A series of 53 HCC patients with early stage (stage 0 according to the Barcelona Clinic Liver Cancer Staging Classification) were selected and then underwent surgery. Tumor tissue samples were evaluated by means of immunohistochemistry and image analysis methods in terms of number of MCDPT, PAR-2-MVD, and C-MVD. RESULTS: A significant correlation between MCDPT, PAR-2-MVD, and C-MVD groups, each correlated to the others, was found by Pearson t-test analysis (r ranged from 0.67 to 0.81; P-value ranged from 0.01 to 0.03). No other significant correlation was found. CONCLUSION: Our in vivo pilot data suggest that MCDPT and PAR-2-MVD may play a role in HCC angiogenesis and could be further evaluated as a target of antiangiogenic therapy.

Mast Cell-Targeted Strategies in Cancer Therapy.

Mast cells (MCs) are cells that originate in the bone marrow from pluripotent CD34+ hematopoietic stem cells. Precursors of MCs migrate through the circulation to their target tissues, completing their maturation process into granulated cells under the influence of several microenvironment growth factors. The most important of these factors is the ligand for the c-Kit receptor (c-Kit-R) namely stem cell factor (SCF), secreted mainly by fibroblasts and endothelial cells (ECs). SCF also regulates development, survival and de novo proliferation of MCs. It has already been demonstrated that gain-of-function mutations of gene c-Kit encoding c-Kit-R result in the development of some tumors. Furthermore, MCs are able also to modulate both innate and adaptive immune response and to express the high-affinity IgE receptor following IgE activation. Among the other IgE-independent MC activation mechanisms, a wide variety of other surface receptors for cytokines, chemokines, immunoglobulins, and complement are also described. Interestingly, MCs can stimulate angiogenesis by releasing of several pro-angiogenic cytokines stored in their cytoplasm. Studies published in the last year suggest that angiogenesis stimulated by MCs may play an important role in tumor growth and progression. Here, we aim to focus several biological features of MCs and to summarize new anti-cancer MC-targeted strategies with potential translation in human clinical trials.

Tumour-associated macrophages correlate with microvascular bed extension in colorectal cancer patients.

Tumour-associated macrophages (TAMs) represent pivotal components of tumour microenvironment promoting angiogenesis, tumour progression and invasion. In colorectal cancer (CRC), there are no conclusive data about the role of TAMs in angiogenesis-mediated tumour progression. In this study, we aimed to evaluate a correlation between TAMs, TAM immunostained area (TAMIA) microvascular density (MVD), endothelial area (EA) and cancer cells positive to VEGF-A (CCP-VEGF-A) in primary tumour tissue of locally advanced CRC patients undergone to radical surgery. A series of 76 patients with CRC were selected and evaluated by immunohistochemistry and image analysis. An anti-CD68 antibody was employed to assess TAMs and TAMIA expression, an anti-CD34 antibody was utilized to detect MVD and EA expression, whereas an anti-VEGF-A antibody was used to detect CCP-VEGF-A; then, tumour sections were evaluated by image analysis methods. The mean ± S.D. of TAMs, MVD and CCP-VEGF-A was 65.58 ± 21.14, 28.53 ± 7.75 and 63% ± 37%, respectively; the mean ± S.D. of TAMIA and EA was 438.37 ± 124.14µ(2) and 186.73 ± 67.22µ(2) , respectively. A significant correlation was found between TAMs, TAMIA, MVD and EA each other (r ranging from 0.69 to 0.84; P ranging from 0.000 to 0.004). The high level of expression of TAMs and TAMIA in tumour tissue and the significant correlation with both MVD and EA illustrate that TAMs could represent a marker that plays an important role in promoting angiogenesis-mediated CRC. In this context, novel agents killing TAMs might be evaluated in clinical trials as a new anti-angiogenic approach.

Mast cells positive to tryptase and tumour-associated macrophages correlate with angiogenesis in locally advanced colorectal cancer patients undergone to surgery.

OBJECTIVE: The density of mast cells positive to tryptase (MCDPT) and tumor-associated macrophages (TAMs) were evaluated in a series of 87 patients with stage B and C colorectal cancer who had undergone radical surgery. METHODS: MCDPT, TAMs, microvascular density (MVD), endothelial area (EA) and CD8(+) tumor infiltrating lymphocytes (CD8(+) TILs) were evaluated in tumor tissue samples by immunohistochemistry and image analysis. Each of the above parameters was correlated with the others and with the main clinico-pathological features. RESULTS: A significant correlation between MCDPT, TAMs, MVD and EA was found by Pearson t-test analysis. With special references to the clinico-pathological features a minimal correlation using univariate analysis was found but it was not retained at multivariate analysis. CONCLUSIONS: Our data suggest that MCDPT and TAMs are linked in the tumor microenvironment and play a role in CRC angiogenesis in a synergistic manner. The assessment of the combination MCDPT and TAMs could be evaluated as a target of novel anti-angiogenic therapies in colorectal cancer patients.

Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients.

Previous experimental and clinical data have indicated that tumour cell proliferation is associated with angiogenesis; in addition, an increased microvascular density (MVD) of tumours has been associated with poor prognosis in solid and haematological malignancies. However, limited data exists regarding the association between tumour cell proliferation and angiogenesis in primary tumour tissue from pancreatic ductal adenocarcinoma (PDAC) patients; therefore, the present study aimed to investigate this association. A series of 31 PDAC patients with stage Tumour (T)2-3 Node (N)0-1 Metastasis (M)0 were recruited into the present study and subsequently underwent surgery. PDAC tissue and adjacent normal tissue (ANT), resected during surgery, were evaluated using immunohistochemistry and image analysis methods to determine MVD, endothelial area (EA) and Ki-67 expression, which is an indicator of cell proliferation rate. The results demonstrated a correlation between the above parameters with each other as well as the main clinico-pathological features of PDAC. Significant differences were identified in MVD, EA and Ki-67 proliferation index between PDAC and ANT. It was demonstrated that MVD, EA and Ki-67 proliferation index were significantly correlated with each other in tumour tissue (r=0.69-0.81; P=0.001-0.003). However, no other significant correlations were identified. These data therefore suggested that angiogenesis and cell proliferation rate were significantly increased in PDAC compared with ANT, which provides a biological basis for the potential use of novel combinations of angiogenesis inhibitors and anti-proliferative chemotherapeutic drugs in the treatment of PDAC.

Infiltrating mast cells correlate with angiogenesis in bone metastases from gastric cancer patients.

While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs) positive for tryptase in bone metastases from gastric cancer patients (BMGCP). It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T3-4N2-3M1 (by AJCC for Gastric Cancer Staging 7th Edition) BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT), MCs area positive to tryptase (MCAPT), microvascular density (MVD) and endothelial area (EA). A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02). Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy.

In vivo model for mastocytosis: A comparative review.

Human mastocytosis are heterogeneous group of neoplastic diseases characterized by a different degree of uncontrolled mast cell (MC) proliferation and activation. Interestingly, human mastocytosis share several biological and clinical features with canine mast cell disorders, so called canine mast cell tumors (CMCTs). These CMCTs are the most common spontaneous cutaneous tumors found in dogs representing a valid model to study neoplastic mast cell disorders. It has been discovered that the pathological activation of c-Kit receptor (c-KitR), expressed by MCs, has been involved in the pathogenesis of neoplastic MC disorders. In this review we have focused on human mastocytosis in terms of: (i) epidemiology and classification; (ii) pathogenesis at molecular levels; (iii) clinical presentation. In addition, we have summarized animal models useful to study neoplastic MC disorders including CMCTs and murine transgenic models. Finally, we have revised therapeutic approaches mostly common in human and canine MCTs and novel tyrosine kinase inhibitors approved for CMCTs and recently translated in human clinical trials.

Targeting endothelial progenitor cells in cancer as a novel biomarker and anti-angiogenic therapy.

Tumoral angiogenesis is mainly an endothelial cell-mediated process, which has been largely demonstrated to take on a crucial role in tumor growth, invasion, and metastasis. Thus, tumor-associated neovasculature represents a pivotal target in cancer therapy. Several mechanisms take part in the genesis of this pathological vasculature, most notably neoangiogenesis and postnatal vasculogenesis. These processes may also play a critical role in the resistance to antiangiogenic agents, leading to tumor progression. In particular, vasculogenesis is mediated by endothelial progenitor cells (EPCs), which include cellular subpopulations with different functional capacities. EPCs are able to proliferate, migrate, and differentiate into mature endothelial cells (ECs) in response to tumor growth, promoting the "angiogenic switch" and, consequently, inducing the invasion and metastases of cancer cells. Therefore, vasculogenesis mediated by EPCs represents an intriguing therapeutic target, both in early and late stages of cancer progression, thereby working as potential landmark for synthesizing novel and more effective anti-angiogenic drugs. Here, we aim to focus and to summarize several biological features of EPCs and EPC-based therapeutic approach with potential translation in human clinical trials.

Serum tryptase, mast cells positive to tryptase and microvascular density evaluation in early breast cancer patients: possible translational significance.

BACKGROUND: Tryptase is a serine protease released from mast cells that plays a role in tumor angiogenesis. In this study we aimed to evaluate serum tryptase levels in 105 female early breast cancer patients before (STLBS) and after (STLAS) radical surgical resection, mast cell density positive to tryptase (MCDPT) and microvascular density (MVD). METHODS: STLBS and STLAS were assessed using the UniCAP Tryptase Fluoroenzyme immunoassay. Tumor sections were immunostained with a primary anti-tryptase antibody and an anti-CD-34 antibody by means of immunohistochemistry. RESULTS: The mean ± 1 standard deviation STLBS and STLAS was 7.18 ± 2.63 µg/L, and 5.13 ± 2.21 respectively and a significant difference between mean levels was found (p = 0.0001) by student t-test. A strong correlation between STLBS and MVD (r = 0.81, p = 0.0001); STLBS and MCDPT (r = 0.69, p = 0.003); and MCDPT and MVD (r = 0.77; p = 0.0001) was found. CONCLUSIONS: Results demonstrated higher STLBS in breast cancer patients, indicating an involvement of MC tryptase in breast cancer angiogenesis. Therefore, serum tryptase levels may play a role as a novel surrogate angiogenic marker predictive of response to radical surgery in breast cancer patients. In this patients setting, it's intriguing to hypothesize that tryptase inhibitors might be evaluated in clinical trials.

Mast cells density positive to tryptase correlates with angiogenesis in pancreatic ductal adenocarcinoma patients having undergone surgery.

Background. Literature data suggest that cells such as mast cells (MCs), are involved in angiogenesis. MCs can stimulate angiogenesis by releasing of several proangiogenic cytokines stored in their cytoplasm. In particular MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor. Nevertheless few data are available concerning the role of MCs positive to tryptase in primary pancreatic cancer angiogenesis. This study analyzed MCs and angiogenesis in primary tumour tissue from patients affected by pancreatic ductal adenocarcinoma (PDAC). Method. A series of 31 PDAC patients with stage T2-3N0-1M0 (by AJCC for Pancreas Cancer Staging 7th Edition) was selected and then underwent surgery. Tumour tissue samples were evaluated by means of immunohistochemistry and image analysis methods in terms of number of MCs positive to tryptase (MCDPT), area occupied by MCs positive to tryptase (MCAPT), microvascular density (MVD), and endothelial area (EA). The above parameters were related to each other and to the main clinicopathological features. Results. A significant correlation between MCDPT, MCAPT, MVD, and EA group was found by Pearson's t-test analysis (r ranged from 0.69 to 0.81; P value ranged from 0.001 to 0.003). No other significant correlation was found. Conclusion. Our pilot data suggest that MCs positive to tryptase may play a role in PDAC angiogenesis and they could be further evaluated as a novel tumour biomarker and as a target of antiangiogenic therapy.