Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing/remodeling to cancer progression1,2. Whereas the mechanism of hypoxia-driven angiogenesis is well understood3,4, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, ω-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles5, are generated during inflammation and wound healing and accumulate at high levels in aging tissues and in highly vascularized tumors. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 nor scavenger receptors on endothelial cells (ECs), leading to a VEGF-independent angiogenic response. CEP promoted angiogenesis in hind limb ischemia and wound healing models through TLR2 signaling in a MyD88-dependent manner. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue re-vascularization and diminished tumor angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.

Angiogenesis alleviates hypoxic stress in ischemic tissues or during tumor progression. In addition to endothelial cell proliferation and migration, the angiogenic process requires bone marrow-derived cell (BMDC) recruitment to sites of neovascularization. However, the mechanism of communication between hypoxic tissues and the BM remains unknown. Using 2 models of hypoxia-induced angiogenesis (ischemic hindlimb surgery and subcutaneous tumor growth), we show that platelet infusion promotes BMDC mobilization into the circulation, BMDC recruitment into growing neovasculature, tumor vascularization, and blood flow restoration in ischemic limbs, whereas platelet depletion inhibits these effects. Thus, platelets are required for BMDC recruitment into ischemia-induced vasculature. Secretion of platelet ␣-granules, but neither dense granules nor platelet aggregation is crucial for BMDC homing and subsequent angiogenesis, as determined using VAMP-8 ؊/؊ , Pearl, and integrin Beta 3 ؊/؊ platelets. Finally, platelets sequester tumor-derived promoters of angiogenesis and BMDC mobilization, which are counterbalanced by the antiangiogenic factor thrombospondin-1. A lack of thrombospondin-1 in platelets leads to an imbalance in proangiogenic and antiangiogenic factors and accelerates tumor growth and vascularization. Our data demonstrate that platelets stimulate BMDC homing in a VAMP-8-dependent manner, revealing a previously unknown role for platelets as key mediators between hypoxic tissues and the bone marrow during angiogenesis. (Blood. 2011;117(14): 3893-3902) IntroductionAngiogenesis, the process of new vessel formation, is necessary for tissue repair after ischemia, myocardial infarction, or during wound healing. Angiogenesis also occurs in various pathologies, including neoplastic growth and retinopathies. Angiogenesis is a systemic process, not limited to existing vasculature expansion, but also involving the recruitment of other cell types, including immune cells, bone marrow-derived cells (BMDCs), and fibroblasts. Because the angiogenesis begins with vascular leakage, the role of blood cells in this process is significant but remains undetermined.We and others have demonstrated the importance of recruited BMDCs in tumor growth and wound healing. [1][2][3] Recruited BMDCs cluster at future metastatic sites before the arrival of tumor cells. 4 In tumors, BMDCs localize to the perivascular area 1,2 and are critical for tumor vessel maturation through cytokine and growth factor secretion. 5,6 In addition, proangiogenic BMDCs accumulate around developing collateral arteries in regenerating myocardial tissues and in ischemic hindlimbs, promoting revascularization. [7][8][9][10] Although the importance of BMDCs in hypoxia-induced angiogenesis is clear, the question of how ischemic tissue communicates with the BM remains unanswered. Although it is logical that the signal for BM to release proangiogenic cells is transmitted by the circulation, there is a need to protect this signal from reaching other parts of the organism a...

Metastatic or recurrent tumors are the primary cause of cancer-related death. For prostate cancer, patients diagnosed with local disease have a 99% 5-year survival rate; however, this 5-year survival rate drops to 28% in patients with metastatic disease. This dramatic decline in survival has driven interest in discovering new markers able to identify tumors likely to recur and in developing new methods to prevent metastases from occurring. Biomarker discovery for aggressive tumor cells includes attempts to identify cancer stem cells (CSCs). CSCs are defined as tumor cells capable of self-renewal and regenerating the entire tumor heterogeneity. Thus, it is hypothesized that CSCs may drive primary tumor aggressiveness, metastatic colonization, and therapeutic relapse. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after therapy allowing for prostate cancer to finally be cured. Here, we will review potential CSC markers and highlight evidence that describes how cells expressing each marker may drive prostate cancer progression, metastatic colonization and growth, tumor recurrence, and resistance to treatment.