Working in the Public Interest Law Conference

Entirely student organized, WIPI seeks to bring together eminent practitioners in their respective fields, students, and faculty to discuss practical approaches to lawyering which can best serve the poor. Practical methods of challenging poverty are often not covered in traditional law school courses. This conference seeks to remedy that and provide dynamic, creative ways to combat poverty through the vehicle of the law

Sequential development of angiotensin receptors and angiotensin I converting enzyme during angiogenesis in the rat subcutaneous sponge granuloma

1. The vasoconstrictor peptide antiotensin II (AII) can stimulate angiogenesis, an important process in wound healing, tumour growth and chronic inflammation. To elucidate mechanisms underlying AII-enhanced angiogenesis, we have studied a subcutaneous sponge granuloma model in the rat by use of (133)Xe clearance, morphometry and quantitative in vitro autoradiography. 2. When injected directly into the sponge, AII (1 nmol day(−1)) increased (133)Xe clearance from, and fibrovascular growth in sponge granulomas, indicating enhanced angiogenesis 6 to 12 days after implantation. This AII-enhanced angiogenesis was inhibited by daily doses (100 nmol/sponge) of the specific but subtype non-selective AII receptor antagonist (Sar(1), Ile(8))AII, and by the selective non-peptide AT(1) receptor antagonists losartan and DuP 532. In contrast, AII-enhanced neovascularization was not inhibited by the AT(2) receptor antagonist PD123319, nor was it mimicked by the AT(2) receptor agonist CGP42112A (each at 100 nmol/sponge day(−1)). 3. AI (1 nmol/sponge day(−1)), the angiotensin converting enzyme (ACE) inhibitors captopril (up to 100 μg/sponge day(−1)) and lisinopril (40 μg/sponge day(−1)), or AII receptor antagonists did not affect angiogenesis in the absence of exogenous AII. 4. [(125)I]-(Sar(1), Ile(8))AII binding sites with characteristics of AT(1) receptors were localized to microvessels and to non-vascular cells within the sponge stroma from 4 days after implantation, and were at higher density than in skin throughout the study. 5. [(125)I]-(Sar(1), Ile(8))AII binding sites with characteristics of AT(2) receptors were localized to non-vascular stromal cells, were of lower density and appeared later than did AT(1) sites. 6. The ACE inhibitor [(125)I]-351A bound to sites with characteristics of ACE, 14 days after sponge implantation. [(125)I]-351A bound less densely to sponge stroma than to skin. 7. We propose that AII can stimulate angiogenesis, acting via AT(1) receptors within the sponge granuloma. AT(1) and AT(2) receptors and ACE develop sequentially during microvascular maturation, and the role of the endogenous angiotensin system in angiogenesis will depend on the balanced local expression of its various components. Pharmacological modulation of this balance may provide novel therapeutic approaches in angiogenesis-dependent diseases

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer