TY - JOUR
T1 - Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis
AU - Fernández-Rodríguez, Rubén
AU - Rodríguez-Baena, Francisco Javier
AU - Martino-Echarri, Estefanía
AU - Peris-Torres, Carlos
AU - Plaza-Calonge, María del Carmen
AU - Rodríguez-Manzaneque, Juan Carlos
N1 - Funding Information:
This work was supported by grants from the Ministerio de Economía y Competitividad and Instituto de Salud Carlos III from Spain, co-financed by FEDER (PI13/00168 to J.C.R.M.), and from the Consejería de Economía, Innovación y Ciencia-Junta de Andalucía (P10-CTS5865 to J.C.R.M.).
PY - 2016/6/7
Y1 - 2016/6/7
N2 - The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1.
AB - The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1.
KW - Extracellular matrix
KW - Extracellular protease
KW - Hypoxia
KW - Tumor stroma
KW - Vasculature
UR - https://www.scopus.com/pages/publications/84973652324
U2 - 10.18632/oncotarget.8922
DO - 10.18632/oncotarget.8922
M3 - Article
C2 - 27120788
AN - SCOPUS:84973652324
SN - 1949-2553
VL - 7
SP - 34507
EP - 34519
JO - Oncotarget
JF - Oncotarget
IS - 23
ER -