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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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Vascularity of tumor sections. LLC1 tumors were sectioned and stained using anti-CD31 antibodies. (A) Section from tumor grown in wild type mouse. (B) Section from tumor grown in Egr-1-/- mouse. (C) Results of blinded counting of sections from three wild type (WT) and Egr-1 knockout (KO) tumors, using either the microvascular density method (MVD), i.e., counting all distinct vessels in a high power field, or the Chalkley method, i.e., placing a gridwork over the photograph and counting those vessels that touch the grid, as described [15]. Values shown are averages and standard deviations.
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Figure 6: Vascularity of tumor sections. LLC1 tumors were sectioned and stained using anti-CD31 antibodies. (A) Section from tumor grown in wild type mouse. (B) Section from tumor grown in Egr-1-/- mouse. (C) Results of blinded counting of sections from three wild type (WT) and Egr-1 knockout (KO) tumors, using either the microvascular density method (MVD), i.e., counting all distinct vessels in a high power field, or the Chalkley method, i.e., placing a gridwork over the photograph and counting those vessels that touch the grid, as described [15]. Values shown are averages and standard deviations.

Mentions: There is evidence that Mig possesses angiostatic properties [3]. We sectioned LLC1 tumors from wild type and Egr-1-/- mice after 12 days of growth, stained for endothelial cells (Figure 6a, b), and measured vascularity both by the microvascular density method and the Chalkley method [15]. There was no significant difference in the vascularity by either approach (Figure 6c).


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

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

Vascularity of tumor sections. LLC1 tumors were sectioned and stained using anti-CD31 antibodies. (A) Section from tumor grown in wild type mouse. (B) Section from tumor grown in Egr-1-/- mouse. (C) Results of blinded counting of sections from three wild type (WT) and Egr-1 knockout (KO) tumors, using either the microvascular density method (MVD), i.e., counting all distinct vessels in a high power field, or the Chalkley method, i.e., placing a gridwork over the photograph and counting those vessels that touch the grid, as described [15]. Values shown are averages and standard deviations.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Vascularity of tumor sections. LLC1 tumors were sectioned and stained using anti-CD31 antibodies. (A) Section from tumor grown in wild type mouse. (B) Section from tumor grown in Egr-1-/- mouse. (C) Results of blinded counting of sections from three wild type (WT) and Egr-1 knockout (KO) tumors, using either the microvascular density method (MVD), i.e., counting all distinct vessels in a high power field, or the Chalkley method, i.e., placing a gridwork over the photograph and counting those vessels that touch the grid, as described [15]. Values shown are averages and standard deviations.
Mentions: There is evidence that Mig possesses angiostatic properties [3]. We sectioned LLC1 tumors from wild type and Egr-1-/- mice after 12 days of growth, stained for endothelial cells (Figure 6a, b), and measured vascularity both by the microvascular density method and the Chalkley method [15]. There was no significant difference in the vascularity by either approach (Figure 6c).

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