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Volume 10, Issue 6, Pages 1032-1042 (December 2004)
Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer Tanya J. Shaw, Mary K. Senterman, Kerri Dawson, Colleen A. Crane, Barbara C. Vanderhyden Molecular Therapy Volume 10, Issue 6, Pages (December 2004) DOI: /j.ymthe Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 1 Survival curves for intraperitoneal xenograft mouse models of ovarian cancer. For each of the 11 cell lines 1 × 107 cells were resuspended in 500 μl of PBS and injected intraperitoneally (day 0) into CD-1 nude mice. The survival curve represents the percentage of animals alive at the indicated time point after injection. The number of mice in each arm is 3, except for ES-2 (n = 5), OV2008 (n = 5), and SKOV3 (n = 7). ▾, ES-2; ●, OCC1; ▴, A2780-cp; ♦, HEY; ▪, A2780-s; □, OVCA 429; ▿, OV2008; ▵, SKOV3. Animals injected with C13*, OVCA 433, and OVCAR3 did not form tumors and are omitted. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 2 Pathological analysis of intraperitoneal xenograft tumors. All tumors were formalin-fixed, paraffin-embedded, sectioned, and stained for analysis and photography. Representative fields of view are shown for each cell type, illustrating the characteristic features used for diagnosis. ES-2 tumors stained for H&E, EMA, LMWK, and VIM are shown in A–D, respectively. H&E-stained sections of an OCC1 tumor are shown in E and F. OVCA 429 tumors stained for H&E, EMA, LMWK, and PAS (diastase-digested negative control in inset) are shown in G–J. The characteristics of the SKOV3 tumors are illustrated by (K) H&E, (L) EMA, (M) LMWK, and (N) PAS (diastase-digested negative control in inset). (O) H&E- and (P) HMWK-stained sections of OV2008 tumors are shown. Original magnifications: C and H, ×100; A, B, D, E, G, I, and J, ×200; F, K, L, M, N, O, and P, ×400. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 3 Circulating human tumor DNA as a diagnostic tool of xenograft models. Plasma was collected from mice prior to A2780-cp ip xenograft and 26 days postxenograft and 1 μl was analyzed by PCR for Alu repeats. The + control lane is a simultaneously performed Alu PCR on genomic DNA extracted from A2780-cp cells in culture, and the − control represents a PCR on genomic DNA from a control mouse ear-punch. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 4 Mice injected ip with A2780-cp present with ovary-specific metastases. 1 × 107 A2780-cp cells were injected ip into a total of 88 CD-1 nude mice and animals were monitored until a predetermined clinical endpoint was reached. Upon necropsy, 12.5% (11 of 88) were found to have severe unilateral or bilateral ovarian disease. The reproductive tracts were removed and photographed (representative photos shown in A and B). Subsequently, all tumor samples were formalin-fixed, paraffin-embedded, sectioned, and H&E stained for histological analysis. (C and D) The bursal membrane appeared structurally intact and the intrabursal space appeared entirely occupied by tumor. The smoothness of the tumor boundary varied from well circumscribed (C) to jagged with migrating cells (D). (E and F) In one case the ovary remained independent of the tumor within the bursal space; the bursal membrane appeared thickened by cancer cells and potentially migrating cells were identified. (G and H) In most cases, normal ovarian structures and follicles were found within the tumors. Original magnifications: C and F, ×25; D, ×400; E, G, and H, ×200. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 5 Mice with A2780-cp xenografts with spontaneous ovarian metastases have a significantly shorter survival time compared to mice with dispersed ip disease. 1 × 107 A2780-cp cells were injected ip into a total of 88 CD-1 nude mice (day 0). The survival curves (dashed line, mice with dispersed ip disease; solid line, mice with ovarian metastases) represent the percentage of animals alive at the indicated time point after injection. The group designated as having ovarian metastases had severe ovarian disease upon necropsy and had a significantly shorter survival time (P < 0.05). The number of mice in each arm is peritoneal, n = 77; ovarian, n = 11. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 6 A2780-cp cell proliferation (Ki67) is higher in ovarian vs peritoneal tumors. All tumors were formalin-fixed, paraffin-embedded, sectioned, and stained for Ki67. Representative fields of view from (A) peritoneal and (B) ovarian A2780-cp tumors are shown (original magnification ×1000). Ki67-positive cells were counted in 10 randomly chosen fields of view of three tumors from different animals for each anatomic location. (C) A significant increase in the number of Ki67-positive cells in the ovarian tumors was observed (P < ). Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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Fig. 7 Gross and microscopic pathology of intrabursal xenograft tumors. At necropsy, the reproductive tract was removed and photographed (A, ES-2; D, OVCA 429; inset of A shows age-matched, uninjected control). Subsequently, all tumor samples were formalin-fixed, paraffin-embedded, sectioned, and H&E stained for histological analysis. The arrows in (B) (ES-2) and (E) (OVCA 429) show normal ovarian follicles identifiable within the sample. One representative field of view of tumor tissue that illustrates the characteristic features used for diagnosis is shown for each cell type (C, ES-2; F, OVCA 429). Scale bar (A and D), 5 mm. Original magnifications: B, C, and E, ×200; F, ×400. Molecular Therapy , DOI: ( /j.ymthe ) Copyright © 2004 The American Society of Gene Therapy Terms and Conditions
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