Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Flister, Michael J.; Tsaih, Shirng Wern; Stoddard, Alexander J.; Jagtap, Jaidip; Parchur, Abdul K.; Sharma, Gayatri; Prisco, Anthony R.; Lemke, Angela; Murphy, Dana; Al-Gizawiy, Mona; Straza, Michael; Ran, Sophia; Geurts, Aron M.; Dwinell, Melinda R.; Greene, Andrew S.; Bergom, Carmen; LaViolette, Peter S.; Joshi, Amit

doi:10.1007/s10549-017-4311-8

Cited by 16 publications

(26 citation statements)

References 34 publications

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“…The RNA-sequencing protocol was previously reported (22,23). Briefly, total RNA was extracted by TRIzol (Thermo Fisher Scientific, Waltham, MA) from the left ventricle tissue of 11-13 weeks old female mock-treated SS and SS.BN3 rats (N = 4-5/group) from a group of rats matched to 1 week post-radiation rats (not reported here, but previously reported).…”

Section: Rna-sequencingmentioning

confidence: 99%

“…We previously reported that the inbred Dahl saltsensitive/Mcwi (SS) rat strain was more sensitive to localized image-guided cardiac radiation than the Brown Norway (BN) strain, and that substitution of chromosome 3 from the BN strain into the SS background (SS.BN3 consomic rats) confers dramatic resistance to radiation-induced cardiac dysfunction when compared to the SS strain (22). Consomic chromosome substitution studies can be used to map complex genetic modifiers of pathophysiologic phenotypes (23)(24)(25)(26). In our previous consomic rat study with the SS strain that was relatively sensitive to localized cardiac radiation when compared to the SS.BN3 consomic strain, the top genetic pathways differentially expressed between SS and SS.BN3 consomic rat ventricles 1 week after radiation included mitochondrial-related genes (22).…”

Section: Introductionmentioning

confidence: 99%

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Differences in Expression of Mitochondrial Complexes Due to Genetic Variants May Alter Sensitivity to Radiation-Induced Cardiac Dysfunction

Schlaak

Frei

SenthilKumar

et al. 2020

Front. Cardiovasc. Med.

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Radiation therapy is received by over half of all cancer patients. However, radiation doses may be constricted due to normal tissue side effects. In thoracic cancers, including breast and lung cancers, cardiac radiation is a major concern in treatment planning. There are currently no biomarkers of radiation-induced cardiotoxicity. Complex genetic modifiers can contribute to the risk of radiation-induced cardiotoxicities, yet these modifiers are largely unknown and poorly understood. We have previously reported the SS (Dahl salt-sensitive/Mcwi) rat strain is a highly sensitized model of radiation-induced cardiotoxicity compared to the more resistant Brown Norway (BN) rat strain. When rat chromosome 3 from the resistant BN rat strain is substituted into the SS background (SS.BN3 consomic), it significantly attenuates radiation-induced cardiotoxicity, demonstrating inherited genetic variants on rat chromosome 3 modify radiation sensitivity. Genes involved with mitochondrial function were differentially expressed in the hearts of SS and SS.BN3 rats 1 week after radiation. Here we further assessed differences in mitochondria-related genes between the sensitive SS and resistant SS.BN3 rats. We found mitochondrial-related gene expression differed in untreated hearts, while no differences in mitochondrial morphology were seen 1 week after localized heart radiation. At 12 weeks after localized cardiac radiation, differences in mitochondrial complex protein expression in the left ventricles were seen between the SS and SS.BN3 rats. These studies suggest that differences in mitochondrial gene expression caused by inherited genetic variants may contribute to differences in sensitivity to cardiac radiation.

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Section: Rna-sequencingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differences in Expression of Mitochondrial Complexes Due to Genetic Variants May Alter Sensitivity to Radiation-Induced Cardiac Dysfunction

Schlaak

Frei

SenthilKumar

et al. 2020

Front. Cardiovasc. Med.

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“…Mcs5a influences tumor progression via the immune system (T cells) in a FBXO10 -dependent manner – analogous to a mechanism in human T lymphocytes (Xu et al, 2014) that is associated with human breast cancer risk (Samuelson et al, 2007). The second modifier locus is linked with DLL4 and impacts breast cancer growth and metastasis by inducing dysfunctional angiogenesis (Flister et al, 2017). A good example from the blood cancer field that may be highly relevant for myeloma is research at the US National Cancer Institute that uncovered the TME risk gene Mndal (myeloid cell nuclear differentiation antigen-like).…”

Section: Current Research Gaps and Future Directionsmentioning

confidence: 99%

Germline Risk Contribution to Genomic Instability in Multiple Myeloma

et al. 2019

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Genomic instability, a well-established hallmark of human cancer, is also a driving force in the natural history of multiple myeloma (MM) – a difficult to treat and in most cases fatal neoplasm of immunoglobulin producing plasma cells that reside in the hematopoietic bone marrow. Long recognized manifestations of genomic instability in myeloma at the cytogenetic level include abnormal chromosome numbers (aneuploidy) caused by trisomy of odd-numbered chromosomes; recurrent oncogene-activating chromosomal translocations that involve immunoglobulin loci; and large-scale amplifications, inversions, and insertions/deletions (indels) of genetic material. Catastrophic genetic rearrangements that either shatter and illegitimately reassemble a single chromosome (chromotripsis) or lead to disordered segmental rearrangements of multiple chromosomes (chromoplexy) also occur. Genomic instability at the nucleotide level results in base substitution mutations and small indels that affect both the coding and non-coding genome. Sometimes this generates a distinctive signature of somatic mutations that can be attributed to defects in DNA repair pathways, the DNA damage response (DDR) or aberrant activity of mutator genes including members of the APOBEC family. In addition to myeloma development and progression, genomic instability promotes acquisition of drug resistance in patients with myeloma. Here we review recent findings on the genetic predisposition to myeloma, including newly identified candidate genes suggesting linkage of germline risk and compromised genomic stability control. The role of ethnic and familial risk factors for myeloma is highlighted. We address current research gaps that concern the lack of studies on the mechanism by which germline risk alleles promote genomic instability in myeloma, including the open question whether genetic modifiers of myeloma development act in tumor cells, the tumor microenvironment (TME), or in both. We conclude with a brief proposition for future research directions, which concentrate on the biological function of myeloma risk and genetic instability alleles, the potential links between the germline genome and somatic changes in myeloma, and the need to elucidate genetic modifiers in the TME.

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“…Such immunocompromised strains are labelled as SS IL2Rγ SS.BN# IL2Rγ . Previous studies on mapping of all BN chromosome substitutions in SS indicated the role of chromosome #3 in inhibiting spontaneous tumoigenesis, murine tumor growth and metastasis [24,25]. We recently demonstrated that human triple-negative breast cancer (TNBC) tumors grown in the SS.BN3 IL2Rγ CXM strain had significantly reduced growth and metastatic progression, reduced expression of notch-pathway gene DLL4 responsible for vascular budding, along with a paradoxical increase in tumor blood vessel density, compared to the parental SS IL2Rγ strain.…”

Section: Introductionmentioning

confidence: 99%

Methods for detecting host genetic modifiers of tumor vascular function using dynamic near-infrared fluorescence imaging

Jagtap¹,

Sharma²,

Parchur³

et al. 2018

Biomed. Opt. Express

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Vascular supply is a critical component of the tumor microenvironment (TME) and is essential for tumor growth and metastasis, yet the endogenous genetic modifiers that impact vascular function in the TME are largely unknown. To identify the host TME modifiers of tumor vascular function, we combined a novel genetic mapping strategy [Consomic Xenograft Model] with near-infrared (NIR) fluorescence imaging and multiparametric analysis of pharmacokinetic modeling. To detect vascular flow, an intensified cooled camera based dynamic NIR imaging system with 785 nm laser diode based excitation was used to image the whole-body fluorescence emission of intravenously injected indocyanine green dye. Principal component analysis was used to extract the spatial segmentation information for the lungs, liver, and tumor regions-of-interest. Vascular function was then quantified by pK modeling of the imaging data, which revealed significantly altered tissue perfusion and vascular permeability that were caused by host genetic modifiers in the TME. Collectively, these data demonstrate that NIR fluorescent imaging can be used as a non-invasive means for characterizing host TME modifiers of vascular function that have been linked with tumor risk, progression, and response to therapy.

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Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer

Abstract: Collectively, these data suggest that host genetic modifier(s) on RNO3 induce nonproductive angiogenesis that inhibits tumor growth through the DLL4 pathway.

Cited by 16 publications

References 34 publications

Differences in Expression of Mitochondrial Complexes Due to Genetic Variants May Alter Sensitivity to Radiation-Induced Cardiac Dysfunction

Differences in Expression of Mitochondrial Complexes Due to Genetic Variants May Alter Sensitivity to Radiation-Induced Cardiac Dysfunction

Germline Risk Contribution to Genomic Instability in Multiple Myeloma

Methods for detecting host genetic modifiers of tumor vascular function using dynamic near-infrared fluorescence imaging

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