Abstract
BackgroundMalignant melanomas frequently metastasize to the brain, but metastases in the cerebellum are underrepresented compared with metastases in the cerebrum.MethodsWe established animal models by injecting intracardially in athymic nude fox1nu mice two human melanoma cell lines, originating from a cerebral metastasis (HM19) and a cerebellar metastasis (HM86).ResultsUsing magnetic resonance imaging (MRI), metastases were first detected after a mean of 34.5 days. Mean survival time was 59.6 days for the mice in the HM86 group and significantly shorter (43.7 days) for HM19‐injected animals (p < 0.001). In the HM86 group, the first detectable metastasis was located in the cerebellum in 15/55 (29%) mice compared with none in the HM19 group (p < 0.001). At sacrifice, cerebellar metastases were found in 34/55 (63%) HM86‐injected mice compared with 1/53 (2%) in the HM19‐injected (p < 0.001) mice. At that time, all mice in both groups had detectable metastases in the cerebrum. Comparing macroscopic and histologic appearances of the brain metastases with their clinical counterparts, the cell line‐based tumors had kept their original morphologic characteristics.ConclusionsThe present work demonstrates that human brain‐metastatic melanoma cells injected intracardially in mice had retained inherent characteristics also in reproducing interaction with subtle microenvironmental brain tissue compartment‐specific features. The models offer new possibilities for investigating tumor‐ and host‐associated factors involved in determining tissue specificity of brain metastasis.
Highlights
The human skin is the largest organ in the body and its melanocytes offer protection against radiation from the sun.1–3 Regretfully, this protection is incomplete and sun exposure is the number one primary cause of cutaneous malignant melanoma (MM) in Caucasians.4,5 Worldwide, the incidence of MM has increased in Caucasian populations over the last 15 years6–10 and it will likely increase further if preventive efforts are not undertaken.11 InNorway, the incidence has increased nearly 15-fold since the Norwegian Cancer Registry was established in 1952, and in the age group 15–54 years, MM is the second most common cancer type for both sexes
It is well known that different cancer types have different propensities for metastasizing to the brain, but most studies do not differentiate between the locations of the metastasis within the various brain compartments
If blood flow or tissue volume was the decisive factor, MM metastases should occur in the cerebrum in 80% of the cases, brain stem in 5%, and cerebellum in 15%
Summary
The human skin is the largest organ in the body and its melanocytes offer protection against radiation from the sun.1–3 Regretfully, this protection is incomplete and sun exposure is the number one primary cause of cutaneous malignant melanoma (MM) in Caucasians. Worldwide, the incidence of MM has increased in Caucasian populations over the last 15 years6–10 and it will likely increase further if preventive efforts are not undertaken. In. 80% of the brain metastases are found in the cerebrum and 20% in the posterior fossa (cerebellum and brain stem).. Rogne et al. found that brain metastases from MMs were significantly underrepresented in the cerebellum, accounting for only 5% of all the intracranial MM metastases resected in their neurosurgical series, and not 15%–20% as might be expected. This reduced propensity of MM to establish growth in the cerebellum is likely associated with microenvironmental and tumor cell-associated factors, in accordance with the seed and soil theory of metastasis. The second objective was to study the relationship between tumor phenotype and metastatic site by morphologic and immunohistochemical analyses, comparing the mouse brain metastases to each other and to the clinical metastases from which the cell lines originated
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