A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients

Wang, J.; Daphu, Inderjit; Pedersen, Paal‐Henning; Miletić, Hrvoje; Hovland, Randi; Mörk, Sverre; Bjerkvig, Rolf; Tiron, Crina; McCormack, Emmet; Micklem, David; Lorens, James B.; Immervoll, Heike; Thorsen, Frits

doi:10.1111/j.1365-2990.2010.01119.x

Cited by 32 publications

(25 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BLI made it possible to visualise disease progression including metastatic dissemination and development of distal metastasis in liver and lungs (Fig. 1B and 4A), and the intensity of the bioluminescence signal correlated with the tumour load [27], [39]–[41]. We subsequently developed a surgical procedure (Fig.…”

Section: Discussionmentioning

confidence: 99%

First In-Mouse Development and Application of a Surgically Relevant Xenograft Model of Ovarian Carcinoma

Helland

Popa²,

Vintermyr

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

PurposePreclinical models of epithelial ovarian cancer have not been exploited to evaluate the clinical standard combination therapy of surgical debulking with follow-up chemotherapy. As surgery is critical to patient survival, here we establish a combined surgical/chemotherapy xenograft model of epithelial ovarian cancer and demonstrate its translational relevance.Experimental DesignSKOV-3luc+ ovary cancer cells were injected topically into the ovaries of immunodeficient mice. Disease development and effect of clinical standard treatment including hysterectomy, bilateral salpingoophorectomy and removal of metastasis with follow up chemotherapy (carboplatin 12 mg/kg + paclitaxel 15 mg/kg) was evaluated by clinical parameters. Tumor burden was quantified by bioluminescence imaging (BLI).ResultsThe xenograft ovarian tumors developed were poorly differentiated and multicystic and the disease disseminated into the peritoneal cavity. When compared to the controls with a mean survival time of 4.9 weeks, mice treated with surgery and chemotherapy, surgery or chemotherapy demonstrated significantly improved mean survival of 16.1 weeks (p = 0.0008), 12.7 weeks (p = 0.0008), or 10.4 weeks (p = 0.008), respectively.ConclusionCombined surgical intervention and adjuvant chemotherapy was demonstrated for the first time in an orthotopic xenograft model of ovarian cancer. Similar to observation in human studies the combined approach resulted in the longest medial survival time, advocating application of this strategy in future preclinical therapeutic development for this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

First In-Mouse Development and Application of a Surgically Relevant Xenograft Model of Ovarian Carcinoma

Helland

Popa²,

Vintermyr

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…The H1 and H3 cell lines were established in our laboratory from patient biopsies of human melanoma brain metastasis, as previously described [31,44]. Written consents were obtained from the patients before tumor material was collected.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

Daphu

Horn

Stieber

et al. 2014

IJMS

View full text Add to dashboard Cite

Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.

show abstract

“…Therefore, establishing patient-derived tumor tissue xenograft models may provide a more accurate reflection of the tumor microenvironment than tumor cell lines [35]. Studies in a variety of tumor types including renal cell, prostate, osteosarcoma, myxoid liposarcoma, brain and uveal melanoma have already demonstrated consistency between clinical tumors and patient-derived xenografts with respect to histological and genetic profiling [36,37,38,39,40,41]. …”

Section: Introductionmentioning

confidence: 99%

Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

Chaudary

Pintilie

Schwock

et al. 2012

Cancers

View full text Add to dashboard Cite

Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model.

show abstract

A novel brain metastases model developed in immunodeficient rats closely mimics the growth of metastatic brain tumours in patients

Abstract: we have developed a representative in vivo model for studying the growth of human metastatic brain cancers. The model described represents an important tool to assess responses to new treatment modalities and for studying mechanisms behind metastatic growth in the central nervous system.

Cited by 32 publications

References 41 publications

First In-Mouse Development and Application of a Surgically Relevant Xenograft Model of Ovarian Carcinoma

First In-Mouse Development and Application of a Surgically Relevant Xenograft Model of Ovarian Carcinoma

In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

Contact Info

Product

Resources

About