An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis

Seth D. Goldstein, Masanori Hayashi, Catherine M. Albert, Kyle W. Jackson, David M. Loeb

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Overall survival rates for pediatric high-grade sarcoma have improved greatly in the past few decades, but prevention and treatment of distant metastasis remain the most compelling problems facing these patients. Traditional preclinical mouse models have not proven adequate to study the biology and treatment of spontaneous distant sarcoma metastasis. To address this deficit, we developed an orthotopic implantation/amputation model in which patient-derived sarcoma xenografts are surgically implanted into mouse hindlimbs, allowed to grow, then subsequently amputated and the animals observed for development of metastases. NOD/SCID/IL-2Rγ-null mice were implanted with either histologically intact high grade sarcoma patient-derived xenografts or cell lines in the pretibial space and affected limbs were amputated after tumor growth. In contrast to subcutaneous flank tumors, we were able to consistently detect spontaneous distant spread of the tumors using our model. Metastases were seen in 27–90 % of animals, depending on the xenograft, and were repeatable and predictable. We also demonstrate the utility of this model for studying the biology of metastasis and present preliminary new insights suggesting the role of arginine metabolism and macrophage phenotype polarization in creating a tumor microenvironment that facilitates metastasis. Subcutaneous tumors express more arginase than inducible nitric oxide synthase and demonstrate significant macrophage infiltration, whereas orthotopic tumors express similar amounts of inducible nitric oxide synthase and arginase and have only a scant macrophage infiltrate. Thus, we present a model of spontaneous distant sarcoma metastasis that mimics the clinical situation and is amenable to studying the biology of the entire metastatic cascade.

Original languageEnglish (US)
Pages (from-to)703-715
Number of pages13
JournalClinical and Experimental Metastasis
Volume32
Issue number7
DOIs
StatePublished - Oct 26 2015
Externally publishedYes

Fingerprint

Tumor Microenvironment
Hindlimb
Amputation
Heterografts
Sarcoma
Neoplasm Metastasis
Arginase
Macrophages
Nitric Oxide Synthase Type II
Neoplasms
Arginine
Survival Rate
Extremities
Pediatrics
Phenotype
Cell Line
Therapeutics
Growth

Keywords

  • Animal model
  • Arginase
  • Ewing sarcoma
  • Metastasis
  • Osteosarcoma
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis. / Goldstein, Seth D.; Hayashi, Masanori; Albert, Catherine M.; Jackson, Kyle W.; Loeb, David M.

In: Clinical and Experimental Metastasis, Vol. 32, No. 7, 26.10.2015, p. 703-715.

Research output: Contribution to journalArticle

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