Escape mechanisms of melanoma from immune system by soluble melanoma antigen

We demonstrate in the B16 melanoma (C57BL/6 derived) system that the soluble form of tumor Ag preferentially suppresses immune responses 1) by inhibiting CTL activity in the effector phase and 2) by induction of specific Ts that block CTL generation in the induction phase. Soluble melanoma antigen Ag injected i.p. into the tumor-bearing host can effectively augment melanoma growth in vivo. Two T cell types with the L3T4+ or double-negative/I-J+ phenotype are involved in the suppression of anti-melanoma CTL responses and can easily be generated in the in vitro primary 12 h-culture. Anti-melanoma Ts recognizes the GM3(NeuAc) structure and distinguishes GM3 molecular species. This is because liposomes constructed with GM3(NeuAc) but not with GM3(NeuGc) gangliosides alone can effectively induce the melanoma-specific Ts. It is thus likely that tumor cells can escape from the immunologic surveillance system by stimulating the repertoire of Ts for self-Ag, GM3, which has existed even in the unprimed conditions in order to maintain self-tolerance. These would appear to be the major escape mechanisms.     

Immuno-diagnosis of malignant melanoma

The diagnosis of malignant melanoma must be followed by treatment shown to be effective. Therefore a correct diagnosis, including staging, that will permit a meaningful prognosis and treatment, is essential. The usefulness and great specificity of immunological methods is based on the detection of antigens characteristic of neoplastic and reactive cells. In cases of malignant melanoma, immunohistochemistry has limited practical value in the routine diagnosis of melanocytic lesions. The method may be important, however, in the differential diagnosis of, for example, malignant melanoma vs. non-melanocytic anaplastic neoplasia, malignant vs. benign melanocytic lesions, etc. Recent advances in relating the immunostaining of antigens to the development of tumor cells, such as proliferation and apoptosis, metastatic potential, etc. have given considerable importance to the immunomorphological evaluation of malignant melanomas. Likewise, immunotherapy requires the immunophenotyping of the reactive cells of the immune system.     

Malignant choroidal melanoma

Malignant choroidal melanoma is the most common primary intraocular malignancy in adults. Controversy has surrounded the treatment and management of these tumors for many years. The Collaborative Ocular Melanoma Study (COMS) is a randomized, controlled, clinical trial funded by the NEI. The study was established to answer the question: what type of treatment is most likely to cause tumor regression, and provide the patient with the best prognosis for cancer free survival? Patients with small tumors were followed annually for 2 years and again 5 years later to determine growth rates for these tumors. Patients with medium, and large tumors are randomized to various treatment strategies. These patients are followed bi-annually with a complete ophthalmic examination and once a year with a complete medical/oncological evaluation. The small tumor arm has completed enrollment with 188 patients. Thirty-one percent of these patients had significant growth of their tumor and were subsequently treated. Final conclusions from the medium tumor arm and the large tumor arm of the trial are pending. A case presentation of a patient with a medium size tumor and an update on the study design and the COMS data gathered to date will be discussed.     

Copper-thionein in melanoma

The phenomenon of an elevated copper concentration in melanoma tumors was examined. It was demonstrated that 50-60% of total tissue copper is associated with metallothionein. The amino acid composition, electronic absorption and fluorescence were identical to that of the many known vertebrate Cu-thioneins. The immunological identification of melanoma tissue metallothionein was successful. The elevated Cu-thionein concentration in melanoma tumor tissue is not yet understood. It appears to be a common concept that in most tumors transient changes of the copper status parallel the metallothionein levels.     

Melanogenesis and melanoma

Melanins are the principal surface pigments in vertebrates and, in humans, play a major role in photoprotection. Although the product (melanin) has a mainly protective function in the skin, the process of melanogenesis represents a potential cellular hazard and is confined to special membrane-limited organelles (melanosomes) in a set of specialized dendritic cells (melanocytes) which synthesize the pigment and transfer it to recipient cells. Malignant melanocytes tend to exhibit up-regulated melanogenesis and defective melanosomes. These features suggest ways in which anti-melanoma therapy may be specifically targeted. Two general chemotherapeutic modalities are considered: 1 The 'Achilles heel' approach in which the generation of reactive quinones capable of leaking into the cytosolic compartment and causing structural and functional derangement is encouraged by the use of analogue substrates. 2 The 'Trojan horse' approach, in which a cytotoxic agent is selectively released by a tyrosinase-dependent mechanism.     

Primary cilium depletion typifies cutaneous melanoma in situ and malignant melanoma

Cutaneous melanoma is a lethal malignancy that arises spontaneously or via in situ precursor neoplasms. While melanoma in situ and locally invasive malignant melanoma can be cured surgically, these lesions can sometimes be difficult to distinguish from melanocytic nevi. Thus, the identification of histolopathologic or molecular features that distinguish these biologically distinct lesions would represent an important advance. To this end, we determined the abundance of melanocytic primary cilia in a series of 62 cases composed of typical cutaneous melanocytic nevi, melanoma in situ, invasive melanoma, and metastatic melanoma. Primary cilia are sensory organelles that modulate developmental and adaptive signaling and notably, are substantially depleted from the neoplastic epithelium of pancreatic carcinoma at a stage equivalent to melanoma in situ. In this series, we find that while nearly all melanocytes in 22 melanocytic nevi possessed a primary cilium, a near-complete loss of this organelle was observed in 16 cases of melanoma in situ, in 16 unequivocal primary invasive melanomas, and in 8 metastatic tumors, each associated with a cutaneous primary lesion. These findings suggest that the primary cilium may be used to segregate cutaneous invasive melanoma and melanoma in situ from melanocytic nevi. Moreover, they place the loss of an organelle known to regulate oncogenic signaling at an early stage of melanoma development.     

Periostin accelerates human malignant melanoma progression by modifying the melanoma microenvironment

Given no reliable therapy for advanced malignant melanoma, it is important to elucidate the molecular mechanisms underlying the disease progression. Using a quantitative proteomics approach, the ‘isobaric tags for relative and absolute quantitation (iTRAQ)’ method, we identified that the extracellular matrix protein, periostin (POSTN), was highly expressed in invasive melanoma compared with normal skin. An immunohistochemical analysis showed that POSTN was expressed in all invasive melanoma (n = 20) and metastatic lymph node (n = 5) tissue samples, notably restricted in their stroma. In terms of the intercellular regulation of POSTN, we found that there was upregulation of POSTN when melanoma cells and normal human dermal fibroblasts (NHDFs) were cocultured, with restricted expression of TGF‐β1 and TGF‐β3. In a functional analyses, recombinant and NHDF‐derived POSTN significantly accelerated melanoma cell proliferation via the integrin/mitogen‐activated protein kinase (MAPK) signaling pathway in vitro. The size of implanted melanoma tumors was significantly suppressed in POSTN/Rag2 double knockout mice compared with Rag2 knock‐out mice. These results indicate that NHDF‐derived POSTN accelerates melanoma progression and might be a promising therapeutic target for malignant melanoma.