The extracellular matrix glycoprotein elastin microfibril interface located protein 2: a dual role in the tumor microenvironment.
We have recently reported that elastin microfibril interface located protein 2 (EMILIN2), an extracellular matrix (ECM) glycoprotein, triggers cell death through a direct binding to death receptors. EMILIN2 thus influences cell viability through a mechanism that is unique for an ECM molecule. In the present work, we report an additional function for this molecule. First, we identify the region responsible for the proapoptotic effects, a 90-amino acid residue-long coiled-coil fragment toward the N-terminus of the molecule. The fragment recapitulates EMILIN2 proapoptotic mechanisms. In addition, using either the full molecule or the active fragment, for the first time, we demonstrate a significant antitumoral effect in vivo, likely due to a decrease in tumor cell viability. Unexpectedly, tumors treated with EMILIN2 or the deletion mutant display a significant increase of tumor angiogenesis. In view of this novel finding, the cotreatment of the growing tumors with an antiangiogenic drug led, in most cases, to a complete regression of tumor growth. These results grant further support to recent findings that pinpoint the microenvironment as an important regulator of cell fate under both physiological and pathological conditions and disclose the possibility of using EMILIN2 fragments as potent antineoplastic tools for cancer treatment.
Mongiat
Maurizio
M
Experimental Oncology Division 2, CRO-IRCCS, Aviano, Italy. mmongiat@cro.it
Marastoni
Stefano
S
Ligresti
Giovanni
G
Lorenzon
Erica
E
Schiappacassi
Monica
M
Perris
Roberto
R
Frustaci
Sergio
S
Colombatti
Alfonso
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; C426245:EMILIN2 protein, human; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D010446:Peptide Fragments