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Background: Promotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC). Methods: A liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA. Results: PR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization. Conclusions: Our results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence. [ABSTRACT FROM AUTHOR]

To examine expression profile and prognostic significance of vascular endothelial growth factor (VEGF) and its receptors in hepatocellular carcinoma (HCC) and peritumoral tissue. Expression of VEGF-A, VEGF-C, and VEGF receptor 1(VEGFR-1), VEGFR-2, and VEGFR-3 in tumor and peritumoral liver tissue was studied by immunohistochemistry in a tissue microarray from 107 patients with HCC. Unsupervised hierarchical cluster analyses were conducted to identify relevant clusters. Staining of VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3 was mostly found on the tumor cells and peritumoral hepatocytes, but VEGFR-1 was mostly expressed in stromal cells. In most of the cases, the expression of VEGF-A, VEGFR-1, VEGFR-2, and VEGFR-3 in was higher in peritumoral liver tissue, while VEGF-C expression was higher in tumor. Unsupervised hierarchical clustering analysis identified four prognostically different clusters, of which cluster A was classified into the “poor prognosis group,” and the other three clusters were classified into the “good prognosis group” ( P = 0.047). Further analysis with a set of seven markers reproduced the same four cluster groups with significantly different recurrence free probability (RFP) ( P = 0.018), and the low RFP group was associated with more intrahepatic satellite lesions. Multivariate analysis showed that classification defined by seven biomarkers was of prognostic significance ( P = 0.000). Expression of VEGF and its receptors was higher in peritumoral tissue than in tumor in HCC. Seven biomarkers predicted patients’ RFP, which consisted of tumoral expression of VEGF-A, VEGFR-1, and VEGF-C as well as peritumoral expression of VEGF-A, VEGFR-1, VEGFR-2, and VEGFR-3. [ABSTRACT FROM AUTHOR]

Staphylococcus Aureus Filtrate Preparation (SAFP) is a preparation of low-virulence strain of Staphylococcus aureus. In our study, we aimed to determine the anti-tumor activity of SAFP in vivo and explore the potential mechanism. Our study evaluated the anti-tumor activity of SAFP in four cancer cell models in vivo and determined its up-regulatory effects on mice immune system in vivo. It showed that 7.2 ng/10 g SAFP could inhibit the progression of murine hepatoma H22 and sarcoma S180, and the tumor inhibition rates achieved 48.1 and 35.7%, respectively. In human non-small cell lung cancer A549 and hepatoma BEL7402 xenograft athymic mice models, T/C of 7.2 ng/10 g SAFP group reached 41.0% in A549 model and 21.0% in BEL7402 model. Meanwhile, SAFP also significantly increased the proliferation of cultured mice splenocytes to 162.1%, and 7.2 ng/kg SAFP significantly ( P < 0.001) raised the activity of NK cells, elevated the serum level of IL-2, TNF-α and IFN-γ in mice. SAFP exhibited high efficiency in inhibiting the growth of cancer cells in a dose-dependent manner, which possibly attributed to its regulatory effects of immune system. [ABSTRACT FROM AUTHOR]