Preclinical xenograft models of human sarcoma show nonrandom loss of aberrations

Abstract

BACKGROUND: Human tumors transplanted into immunodeficient mice (xenografts) are good preclinical models, and it is important to identify possible systematic changes during establishment and passaging in mice. METHODS: High-resolution microarray-based comparative genomic hybridization (array CGH) was used to investigate how well a series of sarcoma xenografts, including 9 patient/xenograft pairs and 8 early versus late xenograft passage pairs, represented the patient tumor from which they originated. RESULTS: In all analyses, the xenografts were more similar to their tumor of origin than other xenografts of the same type. Most changes in aberration patterns were toward a more normal genome complement, and the increased aberrations observed were mostly toward more loss. In general, the changes were scattered over the genome, but some changes were significant in osteosarcomas. These were rather focused and consistent with amplifications frequent in patient samples, involving the genes platelet-derived growth factor receptor A (PDGFRA), cysteine-rich hydrophobic domain 2 (CHIC2), FIP-like 1 (FIP1L1), ligand of numb-protein X1 (LNX1), RAS-like family 11 member B (RASL11B), and sec1 family domain containing 2 (SCFD2), probably a sign of continued tumor progression. Some changes that disappeared may have been involved in host-stroma interactions or chemotherapy resistance, possibly because of the absence of selection in the mouse. CONCLUSIONS: Direct xenografts reflected well the genomic patterns of their tumors of origin. The few significant aberrations that were lost during passaging in immune-defective mice may have been caused by the lack of selection in the new host, whereas aberrations that were gained appeared to be the result of general tumor progression rather than model-specific artifacts. Cancer 2012;118:558-

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

“…Furthermore, both the level of FGF signaling and the actual response to its blockade need to be determined in vivo . Having established xenograft models from this patient tumor as well as from other DDLPS cases [37], we will investigate the effect of FGFR inhibition in vivo in future studies.…”

Animal Models in Osteosarcoma

“…The advantage is that the human malignant cells can grow in its native environment maintaining the heterogeneity that may be required for their proliferation, which in some reports has been shown to enhance tumor growth and metastasis. With the use of cell suspension and transplants, murine host cells can infiltrate the tumor, possibly influencing the activities of the tumor cells, and in some cases, cells of the rodent host can overgrow the human cell population (50). Alternatively orthotopic, intratibial implantation of OS cells has been shown to induce OS at local and metastatic sites (proximal tibia and lung) (43, 51–53).…”

The Role of Immunohistochemistry in Rhabdomyosarcoma Diagnosis Using Tissue Microarray Technology and a Xenograft Model

“…The advantage of xenograft models over in vitro cell lines is that the tumor tissue better resembles the original tumors, and once established, xenograft tumors may be grown indefinitely [17,18,29,30]. Assuming that histology, markers and expression profiles of xenografts are relatively well conserved during xenotransplantation into nude mice, this technique offers the possibility of validating several biomarkers in various tumor samples included in a single TMA [17,18,29,30].…”

“…One disadvantage of xenograft models is that since xenotransplantation is established from small pieces of tissue, they may not correctly represent the original tumor, especially in tumors in which heterogeneity is a more than occasional occurrence [17,18,29,30]. Nevertheless, the procedure adds significant value to the morphological and biological study of human tumors [17,18,29,30], and provides an interesting tool for the study of progression in sarcomas.…”

“…Nevertheless, the procedure adds significant value to the morphological and biological study of human tumors [17,18,29,30], and provides an interesting tool for the study of progression in sarcomas.…”