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.
Highlights
Pancreatic cancer cells have a broad array of cellular defects promoting their uncontrolled growth.Of these, the most extensively studied is the transduction of extracellular growth stimulating signals to the cell nucleus by the HER family of kinases [1,2,3,4,5]
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
ELISA analyses offer compelling evidence that levels of Platelet-derived growth factor receptors β (PDGFr-β) strongly depend on the treatment employed, time elapsed after this treatment, and the source of the receptor, i.e., whether of the human origin derived from tumor cells or of the mouse origin derived from mesenchymal cells of the host (Figure 1)
Summary
Pancreatic cancer cells have a broad array of cellular defects promoting their uncontrolled growth. Platelet-derived growth factor receptors β (PDGFr-β) are involved in the autocrine and paracrine stimulation of solid tumor growth [11]. They regulate cell proliferation and migration, and activate endothelial cells. A great deal of evidence suggests that normal cells from the stroma, including endothelial cells, fibroblasts, immune and inflammatory cells are recruited into pancreatic tumors These various cell types of mesenchymal origin express PDGFr-β and use this signaling loop in the recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. The expression of c-Kit [16] and PDGFr-β [11,17] in a large number of pancreatic cancer biopsies was regarded as an encouraging sign and several clinical protocols involving imatinib were initiated. The comprehensive evaluation, reported here, of the SW1990 tumors reveals unexpected trends in the PDGFr-β expression and activation
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