1. Pathological Significance of Sweat Glands as Melanocytic Stem Cell Niche in the Development of Acral Lentiginous Melanoma in situ
Go J. Yoshida 1), Natsuko Okamoto 1), Takahiro Aoto 1), Toshiaki Saida 1) 2), Emi Nishimura 1)
1) Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU)
2) Department of Dermatology, Shinshu University School of Medicine
Abstract
Result-3: IR-induced differentiation and migration of McSCs
Determination of the origin of cancer remains a challenging issue. Human cutaneous melanoma is a highly aggressive cancer. The preferential proliferation of melanoma cells in the epidermis around sweat ducts is a reliable early diagnostic sign of acral melanoma that affects volar skin. Here, we report the identification of melanocyte stem cells (McSCs) in the secretory portion (SP) of eccrine sweat glands using lineage-tagged H2B-GFP reporter mice. These melanoblasts are normally kept in an immature, slow-cycling state but are able to self-renew in response to genomic stress and provide amplifying progeny to the epidermis where they mature into pigmented melanocytes. FISH analysis of human acral melanoma revealed that McSC-like cells with significant CyclinD1 gene amplification reside deep in the SP of particular gland(s) and further amplification was found in the epidermis of early melanoma lesions, suggesting that McSCs in sweat glands can be an origin of melanoma.
McSCs are transiently activated to respond to endogenous or exogenous genomic stress. GFP+ cells in the SP are able to self-renew to maintain themselves in an immature state and at the same time to provide amplifying and differentiating progeny which migrate up into the epidermis through the sweat ducts
Introduction
Result-4: Molecular pathological analysis of acral melanoma
Both human and mouse volar skin are characterized by a thickened epidermis with rete ridges that extend downward and abundant sweat glands, where pigment-containing cells appear in aged C57/BL6Cr mice.
Specific Aim
To identify the presence of melanocytic stem cells in sweat glands in normal skin, and furthermore, the origin of acral lentiginous melanoma cells and the cause of the dermo-scopic parallel ridge pattern.
Result-1: Melanoblast migration during development
CCND1 gene amplification has been found in % of early acral melanoma cases (North et al., 2008; Takata et al., 2005). DNA-FISH analysis reveaals that CCND1-amplified cells were found in the SP in multiple cases of early acral melanoma which were originally evaluated as melanoma in situ with their contiguous distribution along the duct up to the epidermis.
Slow-cycling melanocytes (immature melanoblasts) stably retain the expression of Histone-GFP fusion protein under control of the Dct promoter with the LCR element once the promoter is activated. Dct-GFP+ population is divided into melanocytic- or schwann-cell lineage, the former of which is Tuj1-.
Conclusion
Result-2: SCF/c-kit-dependent melanoblast survival potential
ACK2 treatment of the neonatal skin depleted almost all GFP+ cells in sweat glands, while ACK2 treatment after the neonatal stage, such as at 7 weeks after birth, did not deplete GFP+ quiescent cells in the sweat glands
On-going Experiments and Future Plan
SPRED, one of the Sprouty family molecules, belongs to the tumor suppressor gene.
NF1 is also reported to be mutated in 10% of melanoma, which is responsible for neurofibromatosis type 1.
c-kit (CD117), the tyrosine kinase receptor which is activated by the ligand SCF (stem cell factor), is hyper-activated in melanoma tissue.
SCF/c-kit dependency
ACK2 is a neutralizing antibody against Kit (c-Kit), which has been used to deplete amplifying melanoblasts in developing skin
McSC differentiation
Nevus in CD117
Eur J Histochem. 2011;55:e20.