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Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice.

Caso G, Barry C, Patejunas G - J Hematol Oncol (2009)

Bottom Line: Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli.Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization.Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Stony Brook University, Stony Brook, NY, USA.giuseppe.caso@stonybrook.edu

ABSTRACT

Background: Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli. Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization. Previous studies have shown that manipulating Egr-1 expression can have either positive or negative effects on tumor growth. We hypothesized that Egr-1 knockout mice might exhibit reduced tumor growth, possibly due to a reduced capacity to respond to angiogenic signals from a growing tumor.

Results: We injected 106 Lewis lung carcinoma (LLC1) cells subcutaneously in the flank of wild type and Egr-1 knockout mice. The average mass of tumors from wild type mice at 12 days after implantation was 413 +/- 128 mg, while those from Egr-1-/- mice was 219 +/- 81 mg (p = 0.001, mean +/- SD). However, sectioning the tumors and staining with anti-CD31 antibodies revealed no difference in the vascularity of the tumors and there was no difference in angiogenic growth factor expression. Expression of the chemokine Mig (CXCL9) was increased 2.8-fold in tumors from knockout mice, but no increase was found in serum levels of Mig. Natural killer cells have a 1.7-fold greater prevalence in the CD45+ cells found in tumors from Egr-1-/- mice compared to those from wild type mice. Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

Conclusion: Mice deficient in Egr-1 exhibit reduced growth of LLC1 tumors, and this phenomenon is associated with overexpression of Mig locally within the tumor. There are no obvious differences in tumor vascularity in the knockout mice. Natural killer cells accumulate in the tumors grown in Egr-1-/- mice, providing a potential mechanism for the reduction in growth.

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Confirmation of Mig expression. Mig was measured using a cytometric bead array. Averages and standard deviations are shown, with p values calculated using Student's t-test. WT = wild type and KO = Egr-1 knockout source animal. (A) Mig in LLC1 tumor lysates, shown as picograms of Mig per microgram of protein. (B) Mig in serum from tumor-bearing mice.
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Figure 3: Confirmation of Mig expression. Mig was measured using a cytometric bead array. Averages and standard deviations are shown, with p values calculated using Student's t-test. WT = wild type and KO = Egr-1 knockout source animal. (A) Mig in LLC1 tumor lysates, shown as picograms of Mig per microgram of protein. (B) Mig in serum from tumor-bearing mice.

Mentions: To confirm the expression levels of Mig, we made additional lysates from LLC1 tumors grown for 11–12 days in wild type and Egr-1-/- mice and measured Mig using a BD cytometric bead array. Levels of Mig were 2.8-fold higher in knockout-derived tumors (Figure 3a). To determine whether this disparity represents a systemic difference in Mig expression between the two types of mice, we also measured Mig in serum from the same animals and found no significant difference (Figure 3b). We attempted to measure Mig in the tissue immediately underlying the tumor (peritoneal wall and associated muscle), but the levels were below the threshold of detection of our assay (data not shown).


Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice.

Caso G, Barry C, Patejunas G - J Hematol Oncol (2009)

Confirmation of Mig expression. Mig was measured using a cytometric bead array. Averages and standard deviations are shown, with p values calculated using Student's t-test. WT = wild type and KO = Egr-1 knockout source animal. (A) Mig in LLC1 tumor lysates, shown as picograms of Mig per microgram of protein. (B) Mig in serum from tumor-bearing mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654460&req=5

Figure 3: Confirmation of Mig expression. Mig was measured using a cytometric bead array. Averages and standard deviations are shown, with p values calculated using Student's t-test. WT = wild type and KO = Egr-1 knockout source animal. (A) Mig in LLC1 tumor lysates, shown as picograms of Mig per microgram of protein. (B) Mig in serum from tumor-bearing mice.
Mentions: To confirm the expression levels of Mig, we made additional lysates from LLC1 tumors grown for 11–12 days in wild type and Egr-1-/- mice and measured Mig using a BD cytometric bead array. Levels of Mig were 2.8-fold higher in knockout-derived tumors (Figure 3a). To determine whether this disparity represents a systemic difference in Mig expression between the two types of mice, we also measured Mig in serum from the same animals and found no significant difference (Figure 3b). We attempted to measure Mig in the tissue immediately underlying the tumor (peritoneal wall and associated muscle), but the levels were below the threshold of detection of our assay (data not shown).

Bottom Line: Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli.Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization.Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Stony Brook University, Stony Brook, NY, USA.giuseppe.caso@stonybrook.edu

ABSTRACT

Background: Early growth response-1 (Egr-1) is an immediate-early transcription factor inducible in the vasculature in response to injury, shear stress, and other stimuli. Mice lacking Egr-1 have a profound deficit in the ability to recover from femoral artery ligation, suggesting a role in neovascularization. Previous studies have shown that manipulating Egr-1 expression can have either positive or negative effects on tumor growth. We hypothesized that Egr-1 knockout mice might exhibit reduced tumor growth, possibly due to a reduced capacity to respond to angiogenic signals from a growing tumor.

Results: We injected 106 Lewis lung carcinoma (LLC1) cells subcutaneously in the flank of wild type and Egr-1 knockout mice. The average mass of tumors from wild type mice at 12 days after implantation was 413 +/- 128 mg, while those from Egr-1-/- mice was 219 +/- 81 mg (p = 0.001, mean +/- SD). However, sectioning the tumors and staining with anti-CD31 antibodies revealed no difference in the vascularity of the tumors and there was no difference in angiogenic growth factor expression. Expression of the chemokine Mig (CXCL9) was increased 2.8-fold in tumors from knockout mice, but no increase was found in serum levels of Mig. Natural killer cells have a 1.7-fold greater prevalence in the CD45+ cells found in tumors from Egr-1-/- mice compared to those from wild type mice. Immunohistochemical staining suggests that Mig expression in the tumors comes from invading macrophages.

Conclusion: Mice deficient in Egr-1 exhibit reduced growth of LLC1 tumors, and this phenomenon is associated with overexpression of Mig locally within the tumor. There are no obvious differences in tumor vascularity in the knockout mice. Natural killer cells accumulate in the tumors grown in Egr-1-/- mice, providing a potential mechanism for the reduction in growth.

Show MeSH
Related in: MedlinePlus