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Am J Cancer Res. 2017 Nov 1;7(11):2333-2349. eCollection 2017.

Bone microenvironment has an influence on the histological response of osteosarcoma to chemotherapy: retrospective analysis and preclinical modeling.

Crenn V1,2,3, Biteau K1,2, Amiaud J1,2, Dumars C4, Guiho R1,2, Vidal L1,2, Nail LL1,2,5, Heymann D1,2, Moreau A4, Gouin F1,2,3, Redini F1,2.

Author information

1
Inserm UMR 1238Nantes, France.
2
Université de Nantes, Bone Sarcomas and Remodeling of Calcified Tissues, Faculté de MédecineNantes, France.
3
Department of Orthopedic, CHU Hôtel DIEUNantes, France.
4
Department of Pathology, CHU Hôtel DIEUNantes, France.
5
Department of Orthopedic, CHU TrousseauTours, France.

Abstract

Osteosarcoma, the most common malignant primary bone tumor, is currently treated with chemotherapy and surgery. The effectiveness of chemotherapy is evaluated by means of histological analysis of tumor necrosis, known as "the Huvos score". However, 25% of the patients initially considered good responders will relapse. In our practice, strong tissue heterogeneity around the residual viable cells of the osteosarcoma is observed, but this is not taken into account by the Huvos score, as it is only an average. The objective is to determine whether heterogeneity in the osteosarcoma's microenvironment can play a role in the histological response to chemotherapy. Two complementary approaches have been developed: (i) the therapeutic response to several monotherapies (ifosfamide, cisplatin, doxorubicin) has been compared to tumor growth and the necrosis levels in different preclinical syngeneic osteosarcoma models, mimicking various microenvironments by injecting the tumor cells into subcutaneous, intra-muscular paratibial, or intra-osseous sites; (ii) a retrospective analysis was performed on patients' osteoblastic osteosarcoma biopsies. Tissue localization mapping of residual live tumor cell colonies was evaluated for potential correlation with overall survival. The results of the preclinical studies showed a difference in tumor growth depending on the osteosarcoma model, with a higher rate in bone sites compared to subcutaneous tumors. For the therapeutic response, a higher response to doxorubicin was observed in the intra-osseous model compared to the intra-muscular model for tumor growth (P = 0.013) and necrosis (P = 0.007). These data strongly suggest that the microenvironment plays a role in how osteosarcoma responds to chemotherapy. The retrospective analysis showed no significant survival difference between residual cell sites, although the soft tissues may be seen as a potential negative factor.

KEYWORDS:

Osteosarcoma; histological analysis; microenvironment; murine model; retrospective analysis

PMID:
29218254
PMCID:
PMC5714759

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