Macrophage migration inhibitory factor (MIF) predicts survival in patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common subtypes of renal cancer, with 30% of patients presenting with systemic disease at diagnosis. This aggressiveness is a consequence of the activation of epithelial-mesenchymal transition (EMT) caused by many different inducers or regulators, signaling cascades, epigenetic regulation, and the tumor environment. Alterations in EMT-related genes and transcription factors are associated with poor prognosis in ccRCC. EMT-related factors suppress E-cadherin expression and are associated with tumor progression, local invasion, and metastasis. The aim of this study was to investigate the expression levels and prognostic significance of macrophage migration inhibitory factor (MIF), ß-catenin, and E-cadherin in ccRCC patients. We examined these proteins immunohistochemically in tumor areas and adjacent normal tissues resected from patients with ccRCC. Analysis of the cancer genome atlas (TCGA) cohort was performed to verify our results. Kaplan-Meier analysis showed that median overall survival (OS) was significantly shorter in patients with tumors exhibiting high MIFn and MIFm-c levels compared to those with low MIFn and MIFm-c levels (p = 0.03 and p = 0.007, respectively). In the TCGA cohort, there was a significant correlation between MIF expression and OS (p < 0.0001). In conclusion, this study provides further evidence for the biological and prognostic value of MIF in the context of EMT as a potential early prognostic marker for advanced-stage ccRCC.

Prognostic significance of SDF-1 chemokine and its receptors CXCR4 and CXCR7 involved in EMT of prostate cancer.

Tendency to conversion from state of chronic inflammation to malignancy is a tumor characteristic trait, which encourages progression to its metastatic stage.. The inflammatory cells maintaining in the tumor inaugurate a communication with cancer cells and become tumor-fostering cells. Epithelial-mesenchymal transition (EMT) is a program supporting malignant cells during switch phenotype into metastatic form, providing looseness of cell-cell adherence and strengthens migratory or invasive features. EMT-undergone tumor cells become more aggressive and resistant to apoptosis. Additionally, malignant cells can be stimulated to manufacture proinflammatory factors throughout EMT program. Chronic inflammation is responsible for EMT induction in malignancies. Developed tumors induce inflammatory response through excretion of cytokines, chemokines and growth factors, which recruit populations of infiltrating immune cells straight to the tumor microenvironment. The inflammatory reaction potentially exerts tumor control, but instead it can be intercepted by the tumor to stimulate its own development in direction to metastatic form. Our study confirmed that SDF-1 chemokine and its receptors, CXCR4 and CXCR7 may participate in initiation of metastases formation and EMT process.

Clinicopathological significance of the EMT-related proteins and their interrelationships in prostate cancer. An immunohistochemical study.

The chronic inflammation influences a microenvironment, where as a result of losing control over tissue homeostatic mechanisms, the carcinogenesis process may be induced. Inflammatory response cells can secrete a number of factors that support both initiation and progression of cancer and also they may consequently induct an epithelial-mesenchymal transition (EMT), the process responsible for development of distant metastasis. Macrophage migration inhibitory factor (MIF) acts as a pro-inflammatory cytokine that is considered as a link between chronic inflammation and tumor development. MIF can function as a modulator of important cancer-related genes expression, as well as an activator of signaling pathways that promotes the development of prostate cancer. The study was performed on FFPE tissues resected from patients who underwent radical prostatectomy. To investigate the relationship of studied proteins with involvement in tumor progression and initiation of epithelial-to-mesenchymal transition (EMT) process, we selected clinicopathological parameters related to tumor progression. Immunohistochemical analyses of MIF, SOX-4, ß-catenin and E-cadherin were performed on TMA slides. We found a statistically significant correlation of overall ß-catenin expression with the both lymph node metastasis (p<0.001) and presence of angioinvasion (p = 0.012). Membrane ß-catenin expression was associated with distant metastasis (p = 0.021). In turn, nuclear MIF was correlated with lymph node metastasis (p = 0.003). The positive protein-protein correlations have been shown between the total ß-catenin protein expression level with level of nuclear SOX-4 protein expression (r = 0.27; p<0.05) as well as negative correlation of ß-catenin expression with level of nuclear MIF protein expression (r = -0.23; p<0.05). Our results seem promising and strongly highlight the potential role of MIF in development of nodal metastases as well as may confirm an involvement of ß-catenin in disease spread in case of prostate cancer.