The molecular and genetic events that contribute to the genesis and progression of
cutaneous malignant melanoma are poorly understood, attributable in large part to the different genetic alterations accompanying
tumorigenesis. Inhibitor of
kinase 4a (INK4a) is often inactivated in families with hereditary
melanoma. Loss of INK4a/alternate reading frame (ARF) in mice is associated with increased incidence of other
tumors such as
lymphoma and
fibrosarcoma. However, the incidence of
melanoma in INK4a/ARF-deficient mice is very low. Our previous studies have revealed that the
CXC chemokine, CXCL1, is overexpressed in human
malignant melanoma cells and is linked to transformation of immortalized murine melanocytes. To study the direct role of CXCL1 on the genesis of primary
melanoma lesions, transgenic mouse lines were established that express the murine homologue of CXCL1,
murine macrophage inflammatory protein 2 (MIP-2), under the transcriptional control of the
tyrosinase promoter/enhancer (Tyr-MIP-2) in the mice that were deficient or not deficient for INK4a/ARF. Strong MIP-2 immunoreactivity was associated with pigmented melanocytes in the hyperproliferative hair follicles in the Tyr-MIP-2 transgenic mice, and the level of MIP-2 expression was similar in both INK4a/ARF heterozygous or wild-type mice.
After treatment of mice with
7,12-dimethylbenz(a)anthracene, cutaneous
melanomas formed in 12% (17/145) of the Tyr-MIP-2 transgene-positive mice, whereas only 2% (3/146) of the Tyr-MIP-2 transgene-negative mice developed
melanoma. When melanocytes cultured from MIP-2 transgenic mice null for INK4a/ARF were transplanted into nude mice,
melanoma formation occurred in 83% (10/12) of the cases with a latency period of 3 months. However, no
melanoma lesions arose in nude mice injected with INK4a/ARF -/- melanocytes, which did not express the MIP-2 transgene. Our results demonstrate that constitutive expression of MIP-2 in INK4a/ARF-deficient melanocytes facilitates formation of
malignant melanoma.