Spontaneous regression of malignant melanoma - is it based on the interplay between host immune system and melanoma antigens?

Malignant melanoma (MM) is the most aggressive and uneasily treatable form of skin cancer. Up to 90% of deaths because of skin tumours are estimated to be caused by this malignancy. Spontaneous regression is described as a partial or complete disappearance of cancer. It can be defined if the clinical and histological diagnosis of malignancy is verified and any therapeutic intervention potentially inducing mechanisms leading to regression has not been applied. Regression occurs more frequently in melanoma than in other types of tumours; it is reported to be six times higher than in other malignancies. Up to 50% of primary MM is reported to undergo spontaneous regression. However, spontaneous regression of the metastatic form of tumour is a rare phenomenon observed in only 0.23% of cases. The most frequently mentioned factors leading to spontaneous regression of MM are operative trauma, infection, vaccination (BCG and rabies vaccines) and immunological factors. Other well-documented circumstances associated with regression of metastatic MM include blood transfusion and various endocrine factors.

Spontaneous regression of tumour and the role of microbial infection--possibilities for cancer treatment.

This review deals with the role of microorganisms in spontaneous regression of a tumour. Spontaneous cancer regression is a phenomenon that has been described for many centuries. One of the most well known methods of inducing spontaneous regression of cancer is the application of Coley's toxin (heat-killed Streptococcus pyogenes and Serratia marcescens), which has been used for the successful treatment of sarcomas, carcinomas, lymphomas, myelomas and melanomas. In clinical practice, the use of Bacillus Calmette-Guérin vaccine for the treatment of superficial urinary bladder cancer is the most common instance of the application of microorganisms for the treatment of cancer. This review provides further information on other tested bacteria--Clostridium spp., Bifidobacterium spp., Lactobacillus spp. and Salmonella spp.--in this field of study. Among new age methods, bactofection, alternative gene therapy, combination bacteriolytic therapy and bacteria-directed enzyme prodrug therapy are some of the potential cancer treatment modalities that use microorganisms. We have also provided information about the interconnection among microorganisms, immune system response, and the possible mechanisms involved in the spontaneous regression of tumours.

Potential novel markers in IBD and CRC diagnostics. Are MMP-19 and RAGE promising candidates?

AIMS: Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. METHODS: Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. RESULTS: There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). CONCLUSION: Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.

Immunohistochemical Evidence of the Involvement of Natural Killer (CD161+) Cells in Spontaneous Regression of Lewis Rat Sarcoma.

BACKGROUND/AIM: Spontaneous regression (SR) of tumours is a rare phenomenon not yet fully understood. The aim of this study was to investigate immune cells infiltrating progressive and SR tumours in a Lewis rat sarcoma model. MATERIALS AND METHODS: Rats were subcutaneously inoculated with rat sarcoma R5-28 (clone C4) cells. Developing tumours were obtained on day 42 and cryosections were immunohistochemically processed for detection of immune cells. RESULTS: A high density of granulocytes was found in the necrotic areas of both progressive and SR tumours. CD4+ cells and CD8+ cells were rare and sparsely dispersed in the tumour tissue without clear difference between the two types of tumours. On the contrary, CD161+ cells were abundant and evenly distributed in SR tumours, but these cells were very rare in progressive tumours. CONCLUSION: Based on the differences in number and distribution of the immune cell subpopulations, we believe that natural killer (CD161+) cells play a major role in the destruction of cancer cells during SR of tumours in this Lewis rat model.

The role of αß T-cells in spontaneous regression of melanoma tumors in swine.

Using a porcine model, we describe Melanoma-Associated CD4+CD8hi T-lymphocytes (MATL) in peripheral blood that increase during melanoma regression. These MATL possess the CD4+CD8hi phenotype and they have their direct counterparts in Tumor Infiltrating Lymphocytes (TIL) isolated from melanoma loci. Both MATL and CD4+CD8hi TIL have a similar expression of selected markers indicating that they represent effector/memory αß T-cell subset. Moreover, although TIL also contain CD4-CD8+ T-cells, only CD4+CD8hi TIL expand during melanoma regression. Importantly, TIL isolated from different pigs and different melanoma loci among the same pig have similar composition of CD4/CD8 subsets, indicating that the composition of the MATL and TIL compartment is identical. Analysis of sorted cells from regressing pigs revealed a unique MATL subpopulation with mono-specific T-cell receptor that was further analyzed by sequencing. These results indicate that pigs regressing melanomas possess a characteristic population of recirculating T-cells playing a role in tumor control and regression.

Melanoma-related changes in skin microbiome.

Melanoma is the least common form of skin tumor, but it is potentially the most dangerous and responsible for the majority of skin cancer deaths. We suggest that the skin microbiome might be changed during the progression of melanoma. The aim of this study is to compare the composition of the skin microbiota between different locations (skin and melanoma) of a MeLiM (Melanoma-bearing Libechov Minipig) pig model (exophytic melanoma). Ninety samples were used for PCR-DGGE analysis with primers specifically targeting the V3 region of the 16S rRNA gene. The profiles were used for cluster analysis by UPGMA and principal coordinate analysis PCoA and also to calculate the diversity index (Simpson index of diversity). By comparing the obtained results, we found that both bacterial composition and diversity were significantly different between the skin and melanoma microbiomes. The abundances of Fusobacterium and Trueperella genera were significantly increased in melanoma samples, suggesting a strong relationship between melanoma development and skin microbiome changes.

Tumour Progression and Spontaneous Regression in the Lewis Rat Sarcoma Model.

Spontaneous regression of tumours is a fascinating phenomenon rarely observed in oncological patients. We used a Lewis rat sarcoma model in which subcutaneous tumours developed after inoculation of the R5-28/clone C4 cells. Rats with tumour progression showed splenomegaly and anaemia. Tumour growth was associated with leucocytosis, granulocytosis, decrease in lymphocyte and CD161(+) population in peripheral blood and increase in serum MCP1 concentration. Animals with spontaneous regression of tumours initially showed an increase in white blood cells number and proportion of granulocytes. Between the 42nd and 49th day, however, values of these parameters dropped in correlation with reduction of tumour size. In spontaneously regressed tumours, vascularization was higher and on the contrary, progressive tumours had more necrotic areas with a high number of infiltrating granulocytes. In conclusion, progression and spontaneous regression of tumours in the Lewis rat sarcoma model is associated with distinct changes in populations of blood cells and immune cells which participate in these completely different processes of tumourigenesis.