An In Vivo Mouse Model for Human Prostate Cancer Metastasis

Havens, Aaron M.; Pedersen, Elisabeth A.; Shiozawa, Yusuke; Cheng, Ying; Jung, Younghun; Sun, Yingxin; Neeley, Chris K.; Wang, Jincheng; Mehra, Rohit; Keller, Evan T.; McCauley, Laurie K.; Loberg, Robert D.; Taichman, Russell S.

doi:10.1593/neo.08154

Cited by 75 publications

(73 citation statements)

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“…To study metastasis formation, xenografted human tumor cells in immunodeficient mice proved to be valuable tools to analyze mechanisms of metastasis in different tumor entities in general (13,26). Yet, the prostate cancer field is critically lacking a metastasis xenograft model, in which human tumor cells can be implanted in vivo and all the steps of the metastatic cascade are mimicked adequately (27). Most of previous attempts used severe combined immunodeficient (SCID) mice and cumbersome procedures (6,28,29), bearing the risk of an artificial route of metastasis delivery in some of these models (5).…”

Section: Discussionmentioning

confidence: 99%

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Lange

Ullrich

Müller

et al. 2012

Clinical Cancer Research

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Purpose: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients.Experimental Design: Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfpÀ/À mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples.Results: PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of b1,6-Nacetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [b(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival.Conclusion: We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of b(1,6)-branched oligosaccharides for prostate cancer progression.

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Section: Discussionmentioning

confidence: 99%

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Lange

Ullrich

Müller

et al. 2012

Clinical Cancer Research

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“…When the animals were sacrificed, tissue samples from the animals' left organ/tissue (original scaffold, calvaria, mandible, humeri, femur, tibia, pelvis, spine, and peripheral blood) were dissected and stored at -80°C until genomic DNA extraction. The number of disseminated cells was assessed by QPCR (16). Further normalization was performed for differences in mouse tissue density using murine β-actin primers.…”

Section: Figurementioning

confidence: 99%

“…SCID mice were used as transplant recipients. 2 vossicles per mouse were implanted into s.c. pouches as previously described (13,16).…”

Section: Figurementioning

confidence: 99%

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Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow

et al. 2011

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HSC homing, quiescence, and self-renewal depend on the bone marrow HSC niche. A large proportion of solid tumor metastases are bone metastases, known to usurp HSC homing pathways to establish footholds in the bone marrow. However, it is not clear whether tumors target the HSC niche during metastasis. Here we have shown in a mouse model of metastasis that human prostate cancer (PCa) cells directly compete with HSCs for occupancy of the mouse HSC niche. Importantly, increasing the niche size promoted metastasis, whereas decreasing the niche size compromised dissemination. Furthermore, disseminated PCa cells could be mobilized out of the niche and back into the circulation using HSC mobilization protocols. Finally, once in the niche, tumor cells reduced HSC numbers by driving their terminal differentiation. These data provide what we believe to be the first evidence that the HSC niche serves as a direct target for PCa during dissemination and plays a central role in bone metastases. Our work may lead to better understanding of the molecular events involved in bone metastases and new therapeutic avenues for an incurable disease. IntroductionMetastases represent the most common malignant tumors involving the skeleton: nearly 70% of patients with breast cancer or prostate cancer (PCa) -and approximately 15%-30% of patients with carcinomas of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney -have bone lesions (1). Several mechanisms are thought to account for the organ-specific nature of bone metastases, including direct tumor extensions, retrograde venous flow, and tumor embolization. It is also clear, however, that anatomy alone does not explain the organ-specific pattern of metastasis.One hypothesis that has gained favor is that the metastatic process is functionally similar to the homing behavior of HSCs to the BM (2, 3). HSC homing, quiescence, and self-renewal in the BM are now known to depend on a region termed the HSC niche (4, 5). Recent studies identified cells of the osteoblastic and endothelial lineages as key components of the niche (6-11). Molecules that play critical roles in HSC niche selection are now thought to be used by metastases to establish footholds in the BM (2, 3), including chemoattractants (CXCL12; also referred to as stromal-derived factor-1; refs. 3, 12), attachment factors (annexin II [Anxa2]; ref. 13), regulators of cell growth, and vascular recruitment ref. 14). Once in the BM, tumor cells parasitize the bone microenvironment to regulate long-term survival/dormancy and, ultimately, metastatic growth. However, it is not known whether metastatic cells specifically target the HSC niche during dissemination.In the present work, we used a PCa model to demonstrate that tumors directly compete with HSCs for occupancy of the endosteal HSC niche during BM transplantation (BMT). Critically, HSCs

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“…25,[63][64][65][66][67][68] It is likely that both these mechanisms could be at play. This question is important to address since current therapies mostly rely on the theory that metastases are similar to the primary tumor from which they arise.…”

Section: Metastasis and Intratumoral Heterogeneitymentioning

confidence: 99%

Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis

Neelakantan¹,

Drasin

Ford³

2014

Cell Adhesion & Migration

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An In Vivo Mouse Model for Human Prostate Cancer Metastasis

Cited by 75 publications

References 20 publications

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Human Prostate Cancer in a Clinically Relevant Xenograft Mouse Model: Identification of β(1,6)-Branched Oligosaccharides as a Marker of Tumor Progression

Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow

Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis

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