Maspin influences response to doxorubicin by changing the tumor microenvironment organization.
Altered degradation and deposition of extracellular matrix are hallmarks of tumor progression and response to therapy. From a microarray supervised analysis on a dataset of chemotherapy-treated breast carcinoma patients, maspin, a member of the serpin protease inhibitor family, has been the foremost variable identified in non-responsive versus responsive tumors. Accordingly, in a series of 52 human breast carcinomas, we detected high maspin expression in tumors that progressed under doxorubicin (DXR)-based chemotherapy. Our analysis of the role of maspin in response to chemotherapy in human MCF7 and MDAMB231 breast and SKOV3 ovarian carcinoma cells transfected to overexpress maspin and injected into mice showed that maspin overexpression led to DXR resistance through the maspin-induced collagen-enriched microenvironment and that an anti-maspin neutralizing monoclonal antibody reversed the collagen-dependent DXR resistance. Impaired diffusion and decreased DXR activity were also found in tumors derived from Matrigel-embedded cells, where abundant collagen fibers characterize the tumor matrix. Conversely, liposome-based DXR reached maspin-overexpressing tumor cells despite the abundant extracellular matrix and was more efficient in reducing tumor growth. Our results identify maspin-induced accumulation of collagen fibers as a cause of disease progression under DXR chemotherapy for breast cancer. Use of a more hydrophilic DXR formulation or of a maspin inhibitor in combination with chemotherapy holds the promise of more consistent responses to maspin-overexpressing tumors and dense-matrix tumors in general.
Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Tiziana
T
Triulzi
Manuela
M
Ratti
Monica
M
Tortoreto
Cristina
C
Ghirelli
Piera
P
Aiello
Viola
V
Regondi
Martina
M
Di Modica
Denis
D
Cominetti
Maria L
ML
Carcangiu
Angela
A
Moliterni
Andrea
A
Balsari
Patrizia
P
Casalini
Elda
E
Tagliabue
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015843:Serpins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; C085344:SERPIN-B5; D015843:Serpins; D004317:Doxorubicin; D003094:Collagen
drug delivery; extracellular matrix; maspin; response to doxorubicin