Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

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Roles of IFN-γ in tumor progression and regression: a review.

Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.

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Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

There is an urgent need for blood-based, noninvasive molecular tests to assist in the detection and diagnosis of cancers in a cost-effective manner at an early stage, when curative interventions are still possible. Additionally, blood-based diagnostics can classify tumors into distinct molecular subtypes and monitor disease relapse and response to treatment. Increasingly, biomarker strategies are becoming critical to identify a specific patient subpopulation that is likely to respond to a new therapeutic agent. The improved understanding of the underlying molecular features of common cancers and the availability of a multitude of recently developed technologies to interrogate the genome, transcriptome, proteome and metabolome of tumors and biological fluids have made it possible to develop clinically applicable and cost-effective tests for many common cancers. Overall, the paradigm shift towards personalized and individualized medicine relies heavily on the increased use of diagnostic biomarkers and classifiers to improve diagnosis, management and treatment. International collaborations, involving both the private and public sector will be required to facilitate the development of clinical applications of biomarkers, using rigorous standardized assays. Here, we review the recent technological and scientific advances in this field.

Emerging molecular biomarkers--blood-based strategies to detect and monitor cancer.

The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.

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Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk.

Ageing is a process characterized by a progressive decline in cellular function, organismal fitness and increased risk of age-related diseases and death. Several hundred theories have attempted to explain this phenomenon. One of the most popular is the 'oxidative stress theory', originally termed the 'free radical theory'. The endocrine system seems to have a role in the modulation of oxidative stress; however, much less is known about the role that oxidative stress might have in the ageing of the endocrine system and the induction of age-related endocrine diseases. This Review outlines the interactions between hormones and oxidative metabolism and the potential effects of oxidative stress on ageing of endocrine organs. Many different mechanisms that link oxidative stress and ageing are discussed, all of which converge on the induction or regulation of inflammation. All these mechanisms, including cell senescence, mitochondrial dysfunction and microRNA dysregulation, as well as inflammation itself, could be targets of future studies aimed at clarifying the effects of oxidative stress on ageing of endocrine glands.

Oxidative stress and the ageing endocrine system

Background: While some risk factors for breast cancer have been confirmed, less is known about the role of early biological and social risk factors for breast cancer in adult life

Methods: In a prospective follow-up in the Northern Finland Birth Cohort 1966 consisting of 5308 women, 120 breast cancers were reported via national registers by the end of 2018 Early risk factors were examined with univariate and multivariate analyses using Cox regression analysis The main results are reported with hazard ratios (HR) and their 95 % confidence intervals (CI) 

Results: In the multivariate-adjusted models, women whose mothers lived in urban areas (HR 168; 95 % CI, 113-251) during pregnancy, were low-educated (HR 240; 95 % CI, 130-445) and had been diagnosed with breast cancer (HR 197; 95 % CI, 109-358), had a higher risk for breast cancer in adult life Lower BMI at the age of 14 associated nonsignificantly with the risk of breast cancer (Mann-Whitney U test, P = 0087) No association between birth size and breast cancer risk in adult life was found

Conclusions: Early-life residence and socioeconomical conditions may have an impact on developing breast cancer in women in adult life All breast cancer cases of this study were relatively young and most of them are assumed to be premenopausal 

Impact: This study is one of a few prospective birth cohort studies to examine early-life socioeconomic factors and breast cancer risk in adult life This study is limited due to small number of cases

Early-Life Risk Factors for Breast Cancer - Prospective Follow-up in the Northern Finland Birth Cohort 1966.

Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient's age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.

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Peeter Karihtala

Papers

Early-Life Risk Factors for Breast Cancer - Prospective Follow-up in the Northern Finland Birth Cohort 1966.

No Association Between Statin Use and the Prognosis of Endometrial Cancer in Women With Type 2 Diabetes.