Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma.
The stromal cells within colon carcinoma express high levels of the platelet-derived growth factor receptor (PDGF-R), whereas colon cancer cells do not. Here, we examined whether blocking PDGF-R could inhibit colon cancer growth in vivo. KM12SM human colon cancer cells were injected subcutaneously (ectopic implantation) into the cecal wall (orthotopic implantation) or into the spleen (experimental liver metastasis) of nude mice. In the colon and liver, the tumors induced active stromal reaction, whereas in the subcutis, the stromal reaction was minimal. Groups of mice (n=10) received saline (control), the tyrosine kinase inhibitor imatinib, irinotecan, or a combination of imatinib and irinotecan. Four weeks of treatment with imatinib and irinotecan significantly inhibited tumor growth (relative to control or single-agent therapy) in the cecum and liver but not in the subcutis. The combination therapy completely inhibited lymph node metastasis. Imatinib alone or in combination with irinotecan inhibited phosphorylation of PDGF-Rbeta of tumor-associated stromal cells and pericytes. Combination therapy also significantly decreased stromal reaction, tumor cell proliferation, and pericyte coverage of tumor microvessels and increased apoptosis of tumor cells and tumor-associated stromal cells. These data demonstrate that blockade of PDGF-R signaling pathways in tumor-associated stromal cells and pericytes inhibits the progressive growth and metastasis of colon cancer cells.
Kitadai
Yasuhiko
Y
Department of Cancer Biology, Unit 173, The University of Texas M.D. Anderson Cancer Center, P.O. Box 302429, Houston, TX 77230-1429, USA.
Sasaki
Takamitsu
T
Kuwai
Toshio
T
Nakamura
Toru
T
Bucana
Corazon D
CD
Fidler
Isaiah J
IJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002277:Carcinoma / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D002432:Cecum / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D000077146:Irinotecan; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020286:Pericytes / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000379:methods
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000077146:Irinotecan; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D002166:Camptothecin