Platelet Angiopoietin-1 Protects Against Murine Models of Tumor Metastasis.

BACKGROUND: In addition to their fundamental roles in preserving vascular integrity, platelets also contribute to tumor angiogenesis and metastasis. However, despite being a reservoir for angiogenic and metastatic cytokines, platelets also harbor negative regulators of tumor progression. Angpt1 (angiopoietin-1) is a cytokine essential for developmental angiogenesis that also protects against tumor cell metastasis through an undefined mechanism. Although activated platelets release Angpt1 from α-granules into circulation, the contributions of platelet Angpt1 to tumor growth, angiogenesis, and metastasis have not been investigated. METHODS: Using cytokine arrays and ELISAs, we first compared platelet Angpt1 levels in breast and melanoma mouse tumor models to tumor-free controls. We then assessed tumor growth and metastasis in mice lacking megakaryocyte and platelet Angpt1 (Angpt1Plt KO). The spontaneous metastasis of mammary-injected tumor cells to the lungs was quantified using RT-PCR (reverse transcription-polymerase chain reaction). The lung colonization of intravenously injected tumor cells and tumor cell extravasation were determined using fluorescent microscopy and flow cytometry. RESULTS: Platelet Angpt1 is selectively upregulated in the PyMT (polyoma middle tumor antigen) breast cancer mouse model, and platelets are the principal source of Angpt1 in blood circulation. While primary tumor growth and angiogenesis were unaffected, Angpt1Plt KO mice had both increased spontaneous lung metastasis and tumor cell lung colonization following mammary or intravenous injection, respectively. Although platelet Angpt1 did not affect initial tumor cell entrapment in the lungs, Angpt1Plt KO mice had increased tumor cell retention and extravasation. Serum from Angpt1Plt KO mice increased endothelial permeability and reduced VE (vascular endothelial)-cadherin expression at endothelial junctions compared with serum from control mice (Angpt1WT). CONCLUSIONS: Platelets provide an intravascular source of Angpt1 that restrains tumor metastasis by preserving the lung microvasculature to limit tumor cell extravasation.

Is atherosclerosis fundamental to human aging? Lessons from ancient mummies.

Case reports from Johan Czermak, Marc Ruffer, and others a century or more ago demonstrated ancient Egyptians had atherosclerosis three millennia ago. The Horus study team extended their findings, demonstrating that atherosclerosis was prevalent among 76 ancient Egyptian mummies and among 61 mummies from each of the ancient cultures of Peru, the American Southwest, and the Aleutian Islands. These findings challenge the assumption that atherosclerosis is a modern disease caused by present day risk factors. An extensive autopsy of an ancient Egyptian teenage male weaver named Nakht found that he was infected with four parasites: Schistosoma haematobium, Taenia species, Trichinella spiralis, and Plasmodium falciparum. Modern day patients with chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus experience premature atherosclerosis. Could the burden of chronic inflammatory disease have been a risk factor for atherosclerosis in these ancient cultures? The prevalence of atherosclerosis in four diverse ancient cultures is consistent with atherosclerosis being fundamental to aging. The impact of risk factors in modern times, and potentially in ancient times, suggests a strong gene-environmental interplay: human genes provide a vulnerability to atherosclerosis, the environment determines when and if atherosclerosis becomes manifest clinically.

Why did ancient people have atherosclerosis?: from autopsies to computed tomography to potential causes.

Computed tomographic findings of atherosclerosis in the ancient cultures of Egypt, Peru, the American Southwest and the Aleutian Islands challenge our understanding of the fundamental causes of atherosclerosis. Could these findings be true? Is so, what traditional risk factors might be present in these cultures that could explain this apparent paradox? The recent computed tomographic findings are consistent with multiple autopsy studies dating as far back as 1852 that demonstrate calcific atherosclerosis in ancient Egyptians and Peruvians. A nontraditional cause of atherosclerosis that could explain this burden of atherosclerosis is the microbial and parasitic inflammatory burden likely to be present in ancient cultures inherently lacking modern hygiene and antimicrobials. Patients with chronic systemic inflammatory diseases of today, including systemic lupus erythematosus, rheumatoid arthritis, and human immunodeficiency virus infection, experience premature atherosclerosis and coronary events. Might the chronic inflammatory load of ancient times secondary to infection have resulted in atherosclerosis? Smoke inhalation from the use of open fires for daily cooking and illumination represents another potential cause. Undiscovered risk factors could also have been present, potential causes that technologically cannot currently be measured in our serum or other tissue. A synthesis of these findings suggests that a gene-environmental interplay is causal for atherosclerosis. That is, humans have an inherent genetic susceptibility to atherosclerosis, whereas the speed and severity of its development are secondary to known and potentially unknown environmental factors.