Dataset Information

Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.

ABSTRACT: BACKGROUND:Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. MATERIALS AND METHODS:Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. RESULTS:Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. CONCLUSION:Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.

SUBMITTER: Atiya HI

PROVIDER: S-EPMC7339129 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.

Atiya Huda I HI Dvorkin-Gheva Anna A Hassell John J Patel Shrusti S Parker Rachel L RL Hartstone-Rose Adam A Hodge Johnie J Fan Daping D Ramsdell Ann F AF

Anticancer research 20190501 5

<h4>Background</h4>Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application.<h4>Materials and methods</h4>Tumors were generated by mammary intraductal (MIND) engraftment of 4T ...[more]

PMID: 31092419

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Project description:BackgroundsPeritoneal invasion in colon cancer is an important prognostic factor. Peritoneal invasion can be objectively identified as periotoneal elastic laminal invasion (ELI) by using elastica stain, and the cancer microenvironment formed by the peritoneal invasion (CMPI) can also be observed. Cases with ELI more frequently show distant metastasis and recurrence. Therefore, CMPI may represent a particular milieu that facilitates tumor progression. Pathological and biological investigations into CMPI may shed light on this possibly distinctive cancer microenvironment.MethodsWe analyzed area-specific tissue microarrays to determine the pathological features of CMPI, and propagated subperitoneal fibroblasts (SPFs) and submucosal fibroblasts (SMFs) from human colonic tissue. Biological characteristics and results of gene expression profile analyses were compared to better understand the peritoneal invasion of colon cancer and how this may form a special microenvironment through the interaction with SPFs. Mouse xenograft tumors, derived by co-injection of cancer cells with either SPFs or SMFs, were established to evaluate their active role on tumor progression and metastasis.ResultsWe found that fibrosis with alpha smooth muscle actin (?-SMA) expression was a significant pathological feature of CMPI. The differences in proliferation and gene expression profile analyses suggested SPFs and SMFs were distinct populations, and that SPFs were characterized by a higher expressions of extracellular matrix (ECM)-associated genes. Furthermore, compared with SMFs, SPFs showed more variable alteration in gene expressions after cancer-cell-conditioned medium stimulation. Gene ontology analysis revealed that SPFs-specific upregulated genes were enriched by actin-binding or contractile-associated genes including ?-SMA encoding ACTA2. Mouse xenograft tumors derived by co-injection of cancer cells with SPFs showed enhancement of tumor growth, metastasis, and capacity for tumor formation compared to those derived from co-injection with cancer cells and SMFs.ConclusionsCMPI is a special microenvironment, and interaction of SPFs and cancer cells within CMPI promote tumor growth and metastasis.

Dataset Information

Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.

Publications

Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.

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