Search

Deficit of oxygen and nutrients in the tumor microenvironment (TME) triggers abnormal angiogenesis that produces dysfunctional and leaky blood vessels, which fail to adequately perfuse tumor tissues. Resulting hypoxia, exacerbation of metabolic disturbances, and generation of an immunosuppressive TME undermine the efficacy of anticancer therapies. Use of carefully scheduled angiogenesis inhibitors has been suggested to overcome these problems and normalize the TME. Here, we propose an alternative agonist-based normalization approach using a derivative of the C-type natriuretic peptide (dCNP). Multiple gene expression signatures in tumor tissues were affected in mice treated with dCNP. In several mouse orthotopic and subcutaneous solid tumor models including colon and pancreatic adenocarcinomas, this well-tolerated agent stimulated formation of highly functional tumor blood vessels to reduce hypoxia. Administration of dCNP also inhibited stromagenesis and remodeling of the extracellular matrix and decreased tumor interstitial fluid pressure. In addition, treatment with dCNP reinvigorated the antitumor immune responses. Administration of dCNP decelerated growth of primary mouse tumors and suppressed their metastases. Moreover, inclusion of dCNP into the chemo-, radio-, or immune-therapeutic regimens increased their efficacy against solid tumors in immunocompetent mice. These results demonstrate the proof of principle for using vasculature normalizing agonists to improve therapies against solid tumors and characterize dCNP as the first in class among such agents. Editor's summary: Tumors often have abnormal and dysfunctional blood vessels that are in part responsible for poor drug delivery and thus reduced efficacy of treatment. Here, Lu et al. have developed a derivative of the C-type natriuretic peptide (dCNP) to normalize vascular structures of tumors to improve therapy efficacy. They demonstrated that this modified dCNP had superior pharmacokinetic and pharmacodynamic properties as compared with native CNP. In addition, administration of dCNP to multiple mouse models remodeled tumor blood vessels and improved antitumorigenic activity of standard monotherapies. This represents a promising compound that could improve therapeutic efficacy of multiple therapies for patients with cancer that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

To understand the larval distribution, size variation, and stable isotope ratios of Japanese eel leptocephali in relation to the salinity front and their feeding ecology, larvae from 7 research cruises (2002–2013) in the North Equatorial Current (NEC) spawning area were examined. The smallest early‐stage larvae were distributed south of or near the salinity front, confirming that the salinity front is an important oceanic feature to understand spawning locations of the Japanese eel. Larger size larvae tended to distribute into higher latitudes. Transport to northern latitudes with their growth would facilitate transport into the Kuroshio region, but retention in the Subtropical Countercurrent (STCC) might be detrimental. Preleptocephalus isotope ratios reflected maternal ratios, but feeding‐stage leptocephali (8–56 mm) tended to have higher ∂15N values at lower latitudes typically in areas south of a salinity front. Feeding larvae quickly assimilate isotope ratios from the NEC after spawning and early growth. Large differences of ∂13C values of larvae between the NEC and STCC might vary with spatial baselines in the two currents. However, diel vertical migrations should be considered, because the isotope ratios in particulate organic matter distinctly depend on the depth. Comparisons among Japanese eel larvae and other taxa of leptocephali in the NEC illustrate the need for further studies on the trophic ecology of leptocephali. [ABSTRACT FROM AUTHOR]