Stefania D'Agostino1,2, Lucia Tombolan2,3, Mattia Saggioro1,2, Chiara Frasson4, Elena Rampazzo2,5, Stefania Pellegrini2, Francesca Favaretto6, Carlo Biz7, Pietro Ruggieri7, Piergiorgio Gamba2, Paolo Bonvini3, Sanja Aveic8,9, Roberto Giovannoni10, Michela Pozzobon1,2. 1. Stem Cells and Regenerative Medicine Lab, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy. 2. Department of Women and Children Health, University of Padova, Padova, Italy. 3. Pediatric Solid Tumors Laboratory, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy. 4. Onco-Hematology Laboratory, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy. 5. Brain Tumors Laboratory, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy. 6. Department of Medicine, Internal Medicine 3, University of Padua, Padua, Italy. 7. Department of Surgery, Oncology and Gastroenterology DiSCOG, Orthopedic Clinic, University of Padova, Padova, Italy. 8. Neuroblastoma Laboratory, Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy. 9. Department of Dental Materials and Biomaterials Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Aachen, Germany. 10. Department of Biology, University of Pisa, Pisa, Italy.
Abstract
BACKGROUND: The interplay between neoplastic cells and surrounding extracellular matrix (ECM) is one of the determinant elements for cancer growth. The remodeling of the ECM by cancer-associated fibroblasts (CAFs) shapes tumor microenvironment by depositing and digesting ECM proteins, hence promoting tumor growth and invasion. While for epithelial tumors CAFs are well characterized, little is known about the stroma composition of mesenchymal cancers, such as in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma during childhood and adolescence. The aim of this work is to identify the importance of CAFs in specifying RMS microenvironment and the role of these stromal cells in RMS growth. METHODS: We assessed in two dimensional (2D) and three dimensional (3D) systems the attraction between RMS cells and fibroblasts using epithelial colon cancer cell line as control. CAFs were studied in a xenogeneic mouse model of both tumor types and characterized in terms of fibroblast activation protein (FAP), mouse PDGFR expression, metalloproteases activation, and ECM gene and protein expression profiling. RESULTS: In 2D model, the rate of interaction between stromal and malignant cells was significantly lower in RMS with respect to colon cancer. Particularly, in 3D system, RMS spheroids tended to dismantle the compact aggregate when grown on the layer of stromal cells. In vivo, despite the well-formed tumor mass, murine CAFs were found in low percentage in RMS xenogeneic samples. CONCLUSIONS: Our findings support the evidence that, differently from epithelial cancers, RMS cells are directly involved in their own ECM remodeling, and less dependent on CAFs support for cancer cell growth.
BACKGROUND: The interplay between neoplastic cells and surrounding extracellular matrix (ECM) is one of the determinant elements for cancer growth. The remodeling of the ECM by cancer-associated fibroblasts (CAFs) shapes tumor microenvironment by depositing and digesting ECM proteins, hence promoting tumor growth and invasion. While for epithelial tumors CAFs are well characterized, little is known about the stroma composition of mesenchymal cancers, such as in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma during childhood and adolescence. The aim of this work is to identify the importance of CAFs in specifying RMS microenvironment and the role of these stromal cells in RMS growth. METHODS: We assessed in two dimensional (2D) and three dimensional (3D) systems the attraction between RMS cells and fibroblasts using epithelial colon cancer cell line as control. CAFs were studied in a xenogeneic mouse model of both tumor types and characterized in terms of fibroblast activation protein (FAP), mouse PDGFR expression, metalloproteases activation, and ECM gene and protein expression profiling. RESULTS: In 2D model, the rate of interaction between stromal and malignant cells was significantly lower in RMS with respect to colon cancer. Particularly, in 3D system, RMS spheroids tended to dismantle the compact aggregate when grown on the layer of stromal cells. In vivo, despite the well-formed tumor mass, murine CAFs were found in low percentage in RMS xenogeneic samples. CONCLUSIONS: Our findings support the evidence that, differently from epithelial cancers, RMS cells are directly involved in their own ECM remodeling, and less dependent on CAFs support for cancer cell growth.
Authors: Zhuan Zhou; Qin Zhou; Xia Wu; San Xu; Xiaohong Hu; Xuxiu Tao; Bo Li; Jinwu Peng; Dan Li; Liangfang Shen; Ya Cao; Lifang Yang Journal: Cancer Lett Date: 2020-01-02 Impact factor: 8.679