Inhibition of p38/MK2 Signaling Prevents Vascular Invasion of Melanoma.

Melanoma cells can switch between distinct gene expression profiles, resulting in proliferative or invasive phenotypes. Signaling pathways involved in this switch were analyzed by gene expression profiling of a cohort of 22 patient-derived melanoma cell lines. CDH1 negativity was identified as a surrogate marker for the invasive phenotype. CDH1 expression could be turned on and off by modulating activity of p38 or its downstream target MK2, suggesting that this pathway controls melanoma progression. Mechanistically, MK2 inhibition prevented melanoma-induced vascular barrier disruption, reduced the expression of PODXL and DEL-1, and prevented vascular dissemination in vivo. PODXL and DEL-1 expression in patients with melanoma were associated with poor survival and thus can be used as prognostic markers. Downstream targets of MK2 may thus serve as candidate therapeutics.

Preventing neurovascular invasion in desmoid tumors.

Desmoid tumors or aggressive fibromatoses are rare, non-encapsulated, infiltrative and locally aggressive tumors originating from deep musculo-aponeurotic structures. Traditionally, preferred treatment method for desmoid tumors is wide local excision. Depending on the side and type of resection, the reported local recurrence rates range from 15 to 77%. Similarly, in our institution there is a significant recurrence rate (24%) in patients who underwent surgery for desmoid tumor. After several recurrences, amputation may be inevitable following repeating vascular and nerve reconstructions. There is a need for a nonviable barrier in order to prevent the invasion of the viable tumor to the neurovascular structures which are also viable tissues. Depending on this need, we present two cases that we used synthetic vascular graft in their operations to cover neurovascular structures in order to prevent tumor invasion. For patients who are not suitable for radiotherapy and the neurovascular structures need to be secured because of the risk of local recurrence, this method can prevent possible future invasion of vessels and nerves.

Mechanisms of inhibition of tumor angiogenesis and vascular tumor growth by epigallocatechin-3-gallate.

PURPOSE: Green tea consumption has been linked to a reduced occurrence of some tumor types. Current data indicate that the principal mediator of this chemopreventive effect is epigallocatechin-3-gallate (EGCG), the most abundant polyphenol found in dried tea leaves. Here, we examined the effects of this compound on the two key cell populations typically involved in tumor growth: tumor cells and endothelial cells. EXPERIMENTAL DESIGN: The effects of green tea and EGCG were tested in a highly vascular Kaposi's sarcoma (KS) tumor model and on endothelial cells in a panel of in vivo and in vitro assays. RESULTS: EGCG inhibited KS-IMM cell growth and endothelial cell growth, chemotaxis, and invasion over a range of doses; high concentrations also induced tumor cell apoptosis. EGCG inhibited the metalloprotease-mediated gelatinolytic activity produced by endothelial cell supernatants and the formation of new capillary-like structures in vitro. Green tea or purified EGCG when administered to mice in the drinking water inhibited angiogenesis in vivo in the Matrigel sponge model and restrained KS tumor growth. Histological analysis of the tumors were consistent with an anti-angiogenic activity of EGCG and green tea. CONCLUSIONS: These data suggest that the green tea gallate or its derivatives may find use in the prevention and treatment of vascular tumors in a chemoprevention or adjuvant setting.

Do conventional pathologic features lose their prognostic significance following postoperative radiation therapy in pathologic stage I-II endometrial adenocarcinoma?

Recent data have suggested that conventional pathologic features (myometrial invasion (MI), grade, stage) lose their prognostic significance following postoperative radiation therapy (RT) in Stage I-II endometrial carcinoma. Our goal was to test this finding in a large cohort of women treated at our institution. Between 1980 and 1997, 188 Stage I (140) and II (48) endometrial adenocarcinoma patients received postoperative RT. RT consisted of pelvic RT (112), vaginal brachytherapy (36), or both (40). Clinicopathologic factors were evaluated as prognostic factors on both univariate and multivariate analyses. Factors correlated with recurrence on univariate analysis included MI (P = 0.05), grade (P = 0.07), lymphovascular invasion (LVI) (P = 0.001) and stage (P = 0.03). Multivariate analysis confirmed the significance of grade (P = 0.02), LVI (P = 0.001), and stage (P = 0.02). Conventional pathologic features do not lose their prognostic significance in pathologic Stage I-II endometrial adenocarcinoma patients following postoperative RT. These factors should continue to be used to identify women at risk for recurrence despite adjuvant RT. New prognostic markers are needed to better identify high-risk patients. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 224-230 (2000).

Treatment of metastatic liver tumors by intermittent repetitive injection of an angiogenesis inhibitor using an implantable port system in a rabbit model.

Angiogenesis inhibitors are expected as a new type of anticancer drug, because they may prevent tumor neovascularization. Among several angiogenesis inhibitors, 6-o-(N-chloroacetylcarbamoyl)-fumagillol (TNP-470) is thought to inhibit the proliferation of migrating endothelial cells, as an aspect of angiogenesis, and attracts an attention for clinical application. We attempted to evaluate anticancer effects of intermittent repetitive intraportal injection of TNP-470 for metastatic liver tumor models and considered the usefulness and a role as an angiogenesis inhibitor, TNP-470, in the anti-cancer therapy using an implantable port system. We used 25 Japanese white rabbits with metastatic liver tumors made by intraportal injection of tumor cells (VX2-carcinoma), and divided those into five groups; group A was control group, group B was treated by repetitive subcutaneous injection of TNP-470 and group C, D, E was treated by repetitive intraportal injection of TNP-470, adriamycin, TNP-470 + adriamycin respectively 5 times at 2 or 3 days interval after tumor inoculation using implantable port systems. After 2 weeks, we evaluated anti-cancer effect of TNP-470 pathologically. In the number of grown tumors, there was no difference among five groups statisitically. But the mean tumor size of each group is smaller in order of group E, D, C, B, A and the differences were significant (P < 0.05) except between E and D group. And intratumoral neovascularization tended to be less in group B, C, E than in group A, D pathologically. We consider that intermittent repetitive injection of TNP-470 is more useful than systemic administration for metastatic liver tumors and the administration of angiogenesis inhibitor with other anti-cancer agents via an implantable port system will be one of the most effective therapeutic methods for them.