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BMC Cancer

, 8:228

First Online: 09 August 2008Received: 24 April 2008Accepted: 09 August 2008DOI: 10.1186-1471-2407-8-228

Cite this article as: Tao, K., Fang, M., Alroy, J. et al. BMC Cancer 2008 8: 228. doi:10.1186-1471-2407-8-228


BackgroundThe 4T1 mouse mammary tumor cell line is one of only a few breast cancer models with the capacity to metastasize efficiently to sites affected in human breast cancer. Here we describe two 4T1 cell lines modified to facilitate analysis of tumor growth and metastasis and evaluation of gene function in vivo. New information regarding the involvement of innate and acquired immunity in metastasis and other characteristics of the model relevant to its use in the study of late stage breast cancer are reported.

MethodsThe lines were engineered for stable expression of firefly luciferase to allow tracking and quantitation of the cells in vivo. Biophotonic imaging was used to characterize growth and metastasis of the lines in vivo and an improved gene expression approach was used to characterize the basis for the metastatic phenotype that was observed.

ResultsGrowth of cells at the primary site was biphasic with metastasis detected during the second growth phase 5–6 weeks after introduction of the cells. Regression of growth, which occurred in weeks 3–4, was associated with extensive necrosis and infiltration of leukocytes. Biphasic tumor growth did not occur in BALB-c SCID mice indicating involvement of an acquired immune response in the effect. Hematopoiesis in spleen and liver and elevated levels of circulating leukocytes were observed at week 2 and increased progressively until death at week 6–8. Gene expression analysis revealed an association of several secreted factors including colony stimulatory factors, cytokines and chemokines, acute phase proteins, angiogenesis factors and ECM modifying proteins with the 4T1 metastatic phenotype. Signaling pathways likely to be responsible for production of these factors were also identified.

ConclusionThe production of factors that stimulate angiogenesis and ECM modification and induce hematopoiesis, recruitment and activation of leukocytes suggest that 4T1 tumor cells play a more direct role than previously appreciated in orchestrating changes in the tumor environment conducive to tumor cell dissemination and metastasis. The new cell lines will greatly facilitate the study of late stage breast and preclinical assessment of cancer drugs and other therapeutics particularly those targeting immune system effects on tumor metastasis.

AbbreviationscRNAcomplementary RNA

DMEMDulbecco-s Minimum Essential Medium

ECMextracellular matrix

FBSfetal bovine serum


FRT siteFLP recombinase targeting site

GEMgenetically engineered mouse

IPAIngenuity Pathway Analysis

MDSCmyeloid derived suppressor cells

NCSnormal calf serum

NEAAnonessential amino acids

PBSphosphate buffered saline

Q-PCRquantitative PCR

ROIregion of interest

siRNAsmall inhibitory RNA

shRNAshort hairpin RNA.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-8-228 contains supplementary material, which is available to authorized users.

Kai Tao, Min Fang contributed equally to this work.

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Autor: Kai Tao - Min Fang - Joseph Alroy - G Gary Sahagian


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