The extracellular matrix protein EMILIN-1 impacts on the microenvironment by hampering gastric cancer development and progression

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 27; no. 5; pp. 1016 - 1030
• Main Authors: Capuano, Alessandra, Vescovo, Maddalena, Canesi, Simone, Pivetta, Eliana, Doliana, Roberto, Nadin, Maria Grazia, Yamamoto, Masami, Tsukamoto, Tetsuya, Nomura, Sachiyo, Pilozzi, Emanuela, Palumbo, Antonio, Canzonieri, Vincenzo, Cannizzaro, Renato, Scanziani, Eugenio, Baldassarre, Gustavo, Mongiat, Maurizio, Spessotto, Paola
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.09.2024; Springer Nature B.V
• Subjects: Abdominal Surgery; Animal models; Animals; Biopsy; Cancer Research; Cancer therapies; Carcinogenesis; Cell culture; Colon cancer; Colorectal cancer; Disease Progression; Elastin microfibril interface located protein; Extracellular matrix; Gastric cancer; Gastroenterology; Humans; Lymphangiogenesis; Matrix protein; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Methylnitrosourea; Mice; Mice, Transgenic; Mutation; N-Methyl-N-nitrosourea; Oncology; Original; Original Article; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Surgical Oncology; Transgenic animals; Transgenic mice; Tumor Microenvironment; Tumorigenesis; Tumors; Extracellular matrix; Tumor microenvironment; Lymphatic vessels; Gastrointestinal intraepithelial neoplasia; Mouse models
• ISSN: 1436-3291; 1436-3305; 1436-3305
• DOI: 10.1007/s10120-024-01528-z

Background The contribution of the tumor microenvironment and extracellular matrix to the aggressive biology of Gastric Cancer (GC) has been recently characterized; however, the role of EMILIN-1 in this context is unknown. EMILIN-1 is an essential structural element for the maintenance of lymphatic vessel (LV) integrity and displays anti-proliferative properties as demonstrated in skin and colon cancer. Given the key role of LVs in GC progression, the aim of this study was to investigate the role of EMILIN-1 in GC mouse models. Methods We used the syngeneic YTN16 cells which were injected subcutaneously and intraperitoneally in genetically modified EMILIN-1 mice. In alternative, carcinogenesis was induced using N -Methyl- N -nitrosourea (MNU). Mouse-derived samples and human biopsies were analyzed by IHC and IF to the possible correlation between EMILIN-1 expression and LV pattern. Results Transgenic mice developed tumors earlier compared to WT animals. 20 days post-injection tumors developed in EMILIN-1 mutant mice were larger and displayed a significant increase of lymphangiogenesis. Treatment of transgenic mice with MNU associated with an increased number of tumors, exacerbated aggressive lesions and higher levels of LV abnormalities. A significant correlation between the levels of EMILIN-1 and podoplanin was detected also in human samples, confirming the results obtained with the pre-clinical models. Conclusions This study demonstrates for the first time that loss of EMILIN-1 in GC leads to lymphatic dysfunction and proliferative advantages that sustain tumorigenesis, and assess the use of our animal model as a valuable tool to verify the fate of GC upon loss of EMILIN-1.