Clinically proven markers of metastasis predict metastatic spread of human melanoma cells engrafted in scid mice

Abstract

Metastasis formation is a complex process and as such can only be modelled in vivo. As markers indicating metastatic spread in syngenic mouse models differ significantly from those in man, this study aimed to develop a human melanoma xenograft mouse model that reflects the clinical situation. Six human melanoma cell lines (LOX, MV3, FEMX-1, G361, MeWo and UISO-Mel6) were xenografted into severe combined immunodeficient mice and tumour growth, metastatic behaviour and number of lung metastases were assessed. Tumours and metastases were analysed for HPA binding and expression of CEACAM-1 and L1, all markers indicative of metastasis in clinical studies. Development of primary tumour nodules ranged from 3 weeks (MV3) to 3 months (MeWo). Whereas G361 and FEMX-1 rarely formed lung metastases, MeWo, MV3 and LOX were moderately and UISO-Mel6 was highly metastatic. Similar to clinical studies, HPA, CEACAM1 and L1 indicated metastatic spread in the xenograft melanoma model, but were not all simultaneously expressed in all cell lines. Considering the strongest expression of one marker combined with an absent or low expression of the other two markers, we conclude that LOX is the cell line of choice for analyses of the functional role of HPA-binding glycoconjugates, UISO-Mel6 is ideally suited to study CEACAM1 function in melanoma spread and L1 function can best be modelled using MeWo. Malignant melanoma, being the most aggressive form of skin cancer, represents a considerable clinical problem worldwide, where about 1 : 35 Caucasians will suffer from malignant melanoma during their lifetime with an incidence furthermore accelerating (Lens and Dawes, 2004). If the primary melanoma can be excised completely before it has spread to distant sites, the patient is cured. However, if metastases occur the patient's fate is sealed, as in spite of intensive research no curative treatment is yet available (Garbe and Blum, 2001;Eigentler et al, 2003). In order to make progress in the field of metastasis treatment, the process of malignant melanoma spread has to be better understood. Metastasis formation is a complex process, which involves many different steps, each of which has to be passed sequentially in order to lead to a clinically detectable metastasis (Hart and Saini, 1992). As this whole metastatic cascade is such a complex process, simple in vitro experiments can only partially mimick the course of metastatic spread and only animal experiments of metastasis can represent the full picture of this multistep phenomenon (Eccles, 2001).In melanoma metastasis research, the mouse B16 melanoma model has found widespread application (Tao et al, 1982). However, as this model represents a syngenic mouse model, it suffers the inherent problems of all murine models of metastasis, namely whether it is directly transferable to humans. Concerning carbohydrate expression, which has profound influence on the metastatic behaviour of tumour cells , murine B16 melanoma cells significantly differ from human melanoma cells. Expression of WGA and PHA...

Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model

“…Mistletoe lectin-I treatment significantly increased the total number of DCs in the PTs of all treatment groups. However, DCs express high numbers of ML-Ibinding sites (Thies et al, 2007b), which is not only the prerequisite for activation by ML-I but also for internalisation of the lectin followed by apoptosis induction in the DCs (see above). We therefore analysed apoptosis rates within the DCs in the different treatment groups, demonstrating that low-dose ML-I (30 ng kg À1 ) protected DCs against apoptosis (apoptosis rate reduced by about 16% compared to control), while higher ML-I doses (150 and 500 ng kg À1 ) significantly increased apoptosis rates in the DCs (Po0.01).…”

“…This cell line has shown both a 100% subcutaneous tumour engraftment and a 100% spontaneous LM rate within 20 days, when engrafted into scid mice (Thies et al, 2007b).…”

“…We have already established a clinically relevant human melanoma xenograft scid mouse model, in which the effects of drugs on melanoma growth and spread can be analysed (Thies et al, 2007b).…”

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

“…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).…”

“…Primary tumors were excised, weighed, and processed for histologic examinations as described before (13,14). Lungs were excised en bloc and fixed in formalin.…”