title: Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer.
abstract: Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment- and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.
authors.affiliation: Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867, Japan. jbaranow@unmc.edu.
authors.forename: Michio
authors.initials: M
authors.lastname: Abe
authors.forename: Zbigniew P
authors.initials: ZP
authors.lastname: Kortylewicz
authors.forename: Charles A
authors.initials: CA
authors.lastname: Enke
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mack
authors.forename: Janina
authors.initials: J
authors.lastname: Baranowska-Kortylewicz