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Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer.

Abe M, Kortylewicz ZP, Enke CA, Mack E, Baranowska-Kortylewicz J - Cancers (Basel) (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867, Japan. jbaranow@unmc.edu.

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.

No MeSH data available.


Related in: MedlinePlus

Expression of various forms of PDGFr-β in lysates prepared from SW1990 human pancreatic adenocarcinoma xenografts extirpated 5 d and 14 d after various treatments and measured using commercial ELISA kits. White bars represent the expression of PDGFr-β in tumors from control mice. Note different scales of the y-axes.
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f1-cancers-03-02501: Expression of various forms of PDGFr-β in lysates prepared from SW1990 human pancreatic adenocarcinoma xenografts extirpated 5 d and 14 d after various treatments and measured using commercial ELISA kits. White bars represent the expression of PDGFr-β in tumors from control mice. Note different scales of the y-axes.

Mentions: ELISA analyses offer compelling evidence that levels of 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). Tumors extirpated from the control mice that received sham IP injections of PBS showed only low levels of human PDGFr-β (Figure 1A) and correspondingly low levels of phosphorylated PDGFr-β (Figure 1B). The magnitude of mouse PDGFr-β expression was nearly identical in all tumor samples recovered five days after the treatment irrespective of what this treatment was (Figure 1C). On the other hand, levels of human PDGFr-β expression greatly depended on the treatment. In tumors recovered five days after treatment, human PDGFr-β levels were 3.4×, 12.4×, and 5.7× higher in the imatinib-treated (light gray bar), 131ICC49 + imatinib-treated (black bar), and 131ICC49-treated mice (dark gray bar), respectively, as compared to PBS-treated control mice (white bar). The receptor phosphorylation followed along the same lines with the treated tumors showing on average 3.1×, 10.3×, and 6.6× higher levels of phosphorylation than tumors from PBS-treated mice demonstrating that the primary response of the tumor tissue to the insult by imatinib or by radiation from 131ICC49 is the increased phosphorylation of the human PDGFr-β receptor. PDGFr-β associated with the stroma, i.e., receptors of the mouse origin, do not seem to respond to any of applied treatments in a major way. No significant deviations in levels of mouse PDGFr-β in treated tumors as compared to those measured in tumors from control mice were detected (Figure 1C).


Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer.

Abe M, Kortylewicz ZP, Enke CA, Mack E, Baranowska-Kortylewicz J - Cancers (Basel) (2011)

Expression of various forms of PDGFr-β in lysates prepared from SW1990 human pancreatic adenocarcinoma xenografts extirpated 5 d and 14 d after various treatments and measured using commercial ELISA kits. White bars represent the expression of PDGFr-β in tumors from control mice. Note different scales of the y-axes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757429&req=5

f1-cancers-03-02501: Expression of various forms of PDGFr-β in lysates prepared from SW1990 human pancreatic adenocarcinoma xenografts extirpated 5 d and 14 d after various treatments and measured using commercial ELISA kits. White bars represent the expression of PDGFr-β in tumors from control mice. Note different scales of the y-axes.
Mentions: ELISA analyses offer compelling evidence that levels of 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). Tumors extirpated from the control mice that received sham IP injections of PBS showed only low levels of human PDGFr-β (Figure 1A) and correspondingly low levels of phosphorylated PDGFr-β (Figure 1B). The magnitude of mouse PDGFr-β expression was nearly identical in all tumor samples recovered five days after the treatment irrespective of what this treatment was (Figure 1C). On the other hand, levels of human PDGFr-β expression greatly depended on the treatment. In tumors recovered five days after treatment, human PDGFr-β levels were 3.4×, 12.4×, and 5.7× higher in the imatinib-treated (light gray bar), 131ICC49 + imatinib-treated (black bar), and 131ICC49-treated mice (dark gray bar), respectively, as compared to PBS-treated control mice (white bar). The receptor phosphorylation followed along the same lines with the treated tumors showing on average 3.1×, 10.3×, and 6.6× higher levels of phosphorylation than tumors from PBS-treated mice demonstrating that the primary response of the tumor tissue to the insult by imatinib or by radiation from 131ICC49 is the increased phosphorylation of the human PDGFr-β receptor. PDGFr-β associated with the stroma, i.e., receptors of the mouse origin, do not seem to respond to any of applied treatments in a major way. No significant deviations in levels of mouse PDGFr-β in treated tumors as compared to those measured in tumors from control mice were detected (Figure 1C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867, Japan. jbaranow@unmc.edu.

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.

No MeSH data available.


Related in: MedlinePlus