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1.
Nat Commun ; 10(1): 2131, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086186

RESUMO

Metastases account for the majority of cancer deaths. While certain steps of the metastatic cascade are well characterized, identification of targets to block this process remains a challenge. Host factors determining metastatic colonization to secondary organs are particularly important for exploration, as those might be shared among different cancer types. Here, we showed that bladder tumor cells expressing the collagen receptor, CD167a, responded to collagen I stimulation at the primary tumor to promote local invasion and utilized the same receptor to preferentially colonize at airway smooth muscle cells (ASMCs)-a rich source of collagen III in lung. Morphologically, COL3-CD167a-driven metastatic foci are uniquely distinct from typical lung alveolar metastatic lesions and exhibited activation of the CD167a-HSP90-Stat3 axis. Importantly, metastatic lung colonization could be abrogated using an investigational drug that attenuates Stat3 activity, implicating this seed-and-soil interaction as a therapeutic target for eliminating lung metastasis.


Assuntos
Colágeno/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Neoplasias Pulmonares/patologia , Miócitos de Músculo Liso/patologia , Neoplasias da Bexiga Urinária/patologia , Animais , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/secundário , Camundongos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Pulm Circ ; 5(2): 382-97, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26064466

RESUMO

Although there are many studies focusing on the molecular pathways underlying lung vascular morphogenesis, the extracellular matrix (ECM)-dependent regulation of mesenchymal cell differentiation in vascular smooth muscle development needs better understanding. In this study, we demonstrate that the paired related homeobox gene transcription factor Prx1 maintains the elastic ECM properties, which are essential for vascular smooth muscle precursor cell differentiation. We have found that Prx1(null) mouse lungs exhibit defective vascular smooth muscle development, downregulated elastic ECM expression, and compromised transforming growth factor (TGF)-ß localization and signaling. Further characterization of ECM properties using decellularized lung ECM scaffolds derived from Prx1 mice demonstrated that Prx1 is required to maintain lung ECM stiffness. The results of cell culture using stiffness-controlled 2-D and 3-D synthetic substrates confirmed that Prx1-dependent ECM stiffness is essential for promotion of smooth muscle precursor differentiation for effective TGF-ß stimulation. Supporting these results, both decellularized Prx1(null) lung ECM and Prx1(WT) (wild type) ECM scaffolds with blocked TGF-ß failed to support mesenchymal cell to 3-D smooth muscle cell differentiation. These results suggest a novel ECM-dependent regulatory pathway of lung vascular development wherein Prx1 regulates lung vascular smooth muscle precursor development by coordinating the ECM biophysical and biochemical properties.

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