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Updated: Mar 1, 2026
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer
Michael J Flister1,2,3, Shirng-Wern Tsaih4,5,6, Alexander Stoddard4
1Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA. mflister@mcw.edu.
Purpose:
Multiple aspects of the tumor microenvironment (TME) impact breast cancer, yet the genetic modifiers of the TME are largely unknown, including those that modify tumor vascular formation and function.
Methods:
To discover host TME modifiers, we developed a system called the Consomic/Congenic Xenograft Model (CXM). In CXM, human breast cancer cells are orthotopically implanted into genetically engineered consomic xenograft host strains that are derived from two parental strains with different susceptibilities to breast cancer. Because the genetic backgrounds of the xenograft host strains differ, whereas the inoculated tumor cells are the same, any phenotypic variation is due to TME-specific modifier(s) on the substituted chromosome (consomic) or subchromosomal region (congenic). Here, we assessed TME modifiers of growth, angiogenesis, and vascular function of tumors implanted in the SSIL2Rγ and SS.BN3IL2Rγ CXM strains.
Results:
Breast cancer xenografts implanted in SS.BN3IL2Rγ (consomic) had significant tumor growth inhibition compared with SSIL2Rγ (parental control), despite a paradoxical increase in the density of blood vessels in the SS.BN3IL2Rγ tumors. We hypothesized that decreased growth of SS.BN3IL2Rγ tumors might be due to nonproductive angiogenesis. To test this possibility, SSIL2Rγ and SS.BN3IL2Rγ tumor vascular function was examined by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analysis of primary blood endothelial cells, all of which revealed altered vascular function in SS.BN3IL2Rγ tumors compared with SSIL2Rγ. Gene expression analysis also showed a dysregulated vascular signaling network in SS.BN3IL2Rγ tumors, among which DLL4 was differentially expressed and co-localized to a host TME modifier locus (Chr3: 95-131 Mb) that was identified by congenic mapping.
Conclusions:
Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.
Insights
Host genetic factors influence breast cancer growth by altering tumor vascularization. Specific genetic modifiers on rat chromosome 3 (RNO3) promote nonproductive angiogenesis, inhibiting tumor progression via the DLL4 pathway.
Area of Science:
- Oncology
- Genetics
- Tumor Microenvironment Research
Background:
- The tumor microenvironment (TME) significantly influences breast cancer progression.
- Genetic modifiers of the TME, particularly those affecting tumor vascularization, remain largely uncharacterized.
Purpose of the Study:
- To identify host genetic modifiers that regulate breast cancer tumor microenvironment, focusing on vascular formation and function.
- To investigate the role of specific genetic loci in modulating tumor growth and angiogenesis.
Main Methods:
- Development and application of the Consomic/Congenic Xenograft Model (CXM) system.
- Orthotopic implantation of human breast cancer cells into genetically distinct rat strains (SSIL2Rγ and SS.BN3IL2Rγ).
- Assessment of tumor growth, angiogenesis, and vascular function using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), micro-computed tomography (micro-CT), and ex vivo analyses.
Main Results:
- Consomic xenografts (SS.BN3IL2Rγ) exhibited significant tumor growth inhibition compared to parental controls (SSIL2Rγ).
- Increased blood vessel density was observed in SS.BN3IL2Rγ tumors, suggesting nonproductive angiogenesis.
- Altered vascular function and a dysregulated vascular signaling network, including differential DLL4 expression, were identified in SS.BN3IL2Rγ tumors.
- Congenic mapping identified a host TME modifier locus on rat chromosome 3 (RNO3).
Conclusions:
- Host genetic modifiers on RNO3 induce nonproductive angiogenesis, thereby inhibiting breast cancer tumor growth.
- The DLL4 pathway is implicated in the mechanism by which these genetic modifiers affect tumor vascularization and growth.
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