Tumor structure and extracellular matrix as a possible barrier for therapeutic approaches using immune cells or adenoviruses in colorectal cancer.
In this article we report about the role that tumor structure and extracellular matrix (ECM) may play in immunotherapy and in gene therapy using adenoviruses. We performed studies in a rat model for colorectal cancer, CC531, and in specimens of human colorectal cancer. The tumors were composed of two compartments, tumor cell nests surrounded by stromal cells. ECM proteins were expressed in the stromal part, where the blood vessels were also located. Furthermore, in several tumors, the tumor cell nests were surrounded by basal membrane-like structures. Therefore, in vascular approaches to treat cancer, therapeutic agents on their route to tumor cells may be hampered by ECM to reach tumor cells. We found that immune cells were abundantly present in tumors from colorectal origin. These cells were, however, not found in direct contact with tumor cells, but mainly in the stromal part of the tumor. Adenoviruses, when intravascularly injected, did not reach tumor cells in the CC531 rat model. Tumor cells were only infected, and even then in limited numbers, in cases of intratumoral injection. We hypothesize that ECM in a tumor is a barrier both for immune cells and for adenoviruses to make direct contact with these tumor cells, and thus limits colorectal tumor therapy.
Kuppen
P J
PJ
Department of Surgery, Leiden University Medical Center, The Netherlands. kuppen@LUMC.nl
van der Eb
M M
MM
Jonges
L E
LE
Hagenaars
M
M
Hokland
M E
ME
Nannmark
U
U
Goldfarb
R H
RH
Basse
P H
PH
Fleuren
G J
GJ
Hoeben
R C
RC
van de Velde
C J
CJ
D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000917:Antibody Formation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000628:therapy; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural; D007763:Lac Operon; D007797:Laminin / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes; D014018:Tissue Distribution
D000912:Antibodies, Neoplasm; D007797:Laminin