Cancer associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAF are `activated' and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma (CCA) as a desmoplastic tumor model, we investigated the sensitivity of liver CAF to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells, but lacked similar effects in quiescent fibroblasts or CCA cells. Unlike CCA cells, niether CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAF or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAF appeared to be due in part to upregulation of the pro-apoptotic protein Bax. shRNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors and apoptotic cell death. In a syngeneic rat model of CCA, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAF in the tumor microenvironment as a general strategy to attack solid tumors.

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Introduction Structural magnetic resonance imaging is a marker of gray matter health and decline that is sensitive to impaired cognition and Alzheimer's disease pathology. Prior work has shown that both amyloid β (Aβ) and tau biomarkers are related to cortical thinning, but it is unclear what unique influences they have on the brain. Methods Aβ pathology was measured with [ 18 F] AV-45 (florbetapir) positron emission tomography (PET) and tau was assessed with [ 18 F] AV-1451 (flortaucipir) PET in a population of 178 older adults, of which 123 had longitudinal magnetic resonance imaging assessments (average of 5.7 years) that preceded the PET acquisitions. Results In cross-sectional analyses, greater tau PET pathology was associated with thinner cortices. When examined independently in longitudinal models, both Aβ and tau were associated with greater antecedent loss of gray matter. However, when examined in a combined model, levels of tau, but not Aβ, were still highly related to change in cortical thickness. Discussion Measures of tau PET are strongly related to gray matter atrophy and likely mediate relationships between Aβ and gray matter.

Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh–treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. Conclusion PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA.