The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.     

Clinical Relevancy of Circulating Tumor Cells in Breast Cancer: Epithelial or Mesenchymal Characteristics,Single Cells or Clusters?

Metastatic breast cancer (MBC) is typically an incurable disease with high mortality rates; thus, early identification of metastatic features and disease recurrence through precise biomarkers is crucial. Circulating tumor cells (CTCs) consisting of heterogeneous subpopulations with different morphology and genetic, epigenetic, and gene expression profiles represent promising candidate biomarkers for metastatic potential. The experimentally verified role of epithelial-to-mesenchymal transition in cancer dissemination has not been clearly described in BC patients, but the stemness features of CTCs strongly contributes to metastatic potency. Single CTCs have been shown to be protected in the bloodstream against recognition by the immune system through impaired interactions with T lymphocytes and NK cells, while associations of heterotypic CTC clusters with platelets, leucocytes, neutrophils, tumor-associated macrophages, and fibroblasts improve their tumorigenic behavior. In addition to single CTC and CTC cluster characteristics, we reviewed CTC evaluation methods and clinical studies in early and metastatic BCs. The variable CTC tests were developed based on specific principles and strategies. However, CTC count and the presence of CTC clusters were shown to be most clinically relevant in existing clinical trials. Despite the known progress in CTC research and sampling of BC patients, implementation of CTCs and CTC clusters in routine diagnostic and treatment strategies still requires improvement in detection sensitivity and precise molecular characterizations, focused predominantly on the role of CTC clusters for their higher metastatic potency.     

Inositol (1,4,5)-Trisphosphate Receptors in Invasive Breast Cancer: A New Prognostic Tool?

Simple SummaryThe inositol-trisphosphate receptor (IP₃R) is a key player in physiological and pathological intracellular calcium signaling. The objective of the present study was to assess the putative value of the three IP₃R subtypes as prognostic biomarkers in breast cancer. We found that IP₃R3 is the most strongly expressed subtype in breast cancer tissue. Furthermore, IP₃R3 and IP₃R1 are significantly more expressed in invasive breast cancer tissue than in non-tumor tissue. In contrast to IP₃R1 and IP₃R2, the expression of IP₃R3 was positively correlated with prognostic factors including tumor size, regional node invasion, histologic grade, proliferation index, and hormonal status. By analyzing public databases, we found that the expression of all IP₃R subtypes is significantly correlated with the overall survival and disease-free survival of patients with breast cancer. We conclude that relative to the other two IP₃R subtypes, IP₃R3 expression is upregulated in breast cancer and is correlated with prognostic factors. We strongly believe that our results will open up new perspectives with regard to the link between IP₃Rs and breast cancer aggressiveness.AbstractBreast cancer is the leading cause of cancer death among women in worldwide and France. The disease prognosis and treatment differ from one breast cancer subtype to another, and the disease outcome depends on many prognostic factors. Deregulation of ion flux (especially Ca²⁺ flux) is involved in many pathophysiology processes, including carcinogenesis. Inside the cell, the inositol-trisphosphate receptor (IP₃R) is a major player in the regulation of the Ca²⁺ flux from the endoplasmic reticulum to the cytoplasm. The IP₃Rs (and particularly the IP₃R3 subtype) are known to be involved in proliferation, migration, and invasion processes in breast cancer cell lines. The objective of the present study was to evaluate the potential value of IP₃Rs as prognostic biomarkers in breast cancer. We found that expression levels of IP₃R3 and IP₃R1 (but not IP₃R2) were significantly higher in invasive breast cancer of no special type than in non-tumor tissue from the same patient. However, the IP₃R3 subtype was expressed more strongly than the IP₃R1 and IP₃R2 subtypes. Furthermore, the expression of IP₃R3 (but not of IP₃R1 or IP₃R2) was positively correlated with prognostic factors such as tumor size, regional node invasion, histologic grade, proliferation index, and hormone receptor status. In an analysis of public databases, we found that all IP₃Rs types are significantly associated with overall survival and progression-free survival in patients with breast cancer. We conclude that relative to the other two IP₃R subtypes, IP₃R3 expression is upregulated in breast cancer and is correlated with prognostic factors.     

Breast Cancer and Microcalcifications: An Osteoimmunological Disorder?

The presence of microcalcifications in the breast microenvironment, combined with the growing evidences of the possible presence of osteoblast-like or osteoclast-like cells in the breast, suggest the existence of active processes of calcification in the breast tissue during a woman’s life. Furthermore, much evidence that osteoimmunological disorders, such as osteoarthritis, rheumatoid arthritis, or periodontitis influence the risk of developing breast cancer in women exists and vice versa. Antiresorptive drugs benefits on breast cancer incidence and progression have been reported in the past decades. More recently, biological agents targeting pro-inflammatory cytokines used against rheumatoid arthritis also demonstrated benefits against breast cancer cell lines proliferation, viability, and migratory abilities, both in vitro and in vivo in xenografted mice. Hence, it is tempting to hypothesize that breast carcinogenesis should be considered as a potential osteoimmunological disorder. In this review, we compare microenvironments and molecular characteristics in the most frequent osteoimmunological disorders with major events occurring in a woman’s breast during her lifetime. We also highlight what the use of bone anabolic drugs, antiresorptive, and biological agents targeting pro-inflammatory cytokines against breast cancer can teach us.     

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.     

Targeting Inflammation after Myocardial Infarction: A Therapeutic Opportunity for Extracellular Vesicles?

After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac remodeling and heart failure post-MI. The present challenge is to find a way to stimulate this process without interfering with the reparative role of the immune system. Extracellular vesicles (EVs) are natural membrane particles that are released by cells and carry different macromolecules, including proteins and non-coding RNAs. In recent years, EVs derived from various stem and progenitor cells have been demonstrated to possess regenerative properties. They can provide cardioprotection via several mechanisms of action, including immunomodulation. In this review, we summarize the role of the innate immune system in post-MI healing. We then discuss the mechanisms by which EVs modulate cardiac inflammation in preclinical models of myocardial injury through regulation of monocyte influx and macrophage function. Finally, we provide suggestions for further optimization of EV-based therapy to improve its potential for the treatment of MI.     

Organometallic Compounds: An Opportunity for Chemical Biology?

Organometallic compounds are renowned for their remarkable applications in the field of catalysis, but much less is known about their potential in chemical biology. Indeed, such compounds have long been considered to be either unstable under physiological conditions or cytotoxic. As a consequence, little attention has been paid to their possible utilisation for biological purposes. Because of their outstanding physicochemical properties, which include chemical stability, structural diversity and unique photo- and electrochemical properties, however, organometallic compounds have the ability to play a leading role in the field of chemical biology. Indeed, remarkable examples of the use of such compounds-notably as enzyme inhibitors and as luminescent agents-have recently been reported. Here we summarise recent advances in the use of organometallic compounds for chemical biology purposes, an area that we define as "organometallic chemical biology". We also demonstrate that these recent discoveries are only a beginning and that many other organometallic complexes are likely to be found useful in this field of research in the near future.     

Metformin and Breast Cancer: Where Are We Now?

Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.     

Infections and Immunotherapy in Lung Cancer: A Bad Relationship?

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients’ prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.     

Autophagy: A Friend or Foe in Allergic Asthma?

Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.     

Gene Therapy Targeting p53 and KRAS for Colorectal Cancer Treatment: A Myth or the Way Forward?

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and is responsible as one of the main causes of mortality in both men and women. Despite massive efforts to raise public awareness on early screening and significant advancements in the treatment for CRC, the majority of cases are still being diagnosed at the advanced stage. This contributes to low survivability due to this cancer. CRC patients present various genetic changes and epigenetic modifications. The most common genetic alterations associated with CRC are p53 and KRAS mutations. Gene therapy targeting defect genes such as TP53 (tumor suppressor gene encodes for p53) and KRAS (oncogene) in CRC potentially serves as an alternative treatment avenue for the disease in addition to the standard therapy. For the last decade, significant developments have been seen in gene therapy for translational purposes in treating various cancers. This includes the development of vectors as delivery vehicles. Despite the optimism revolving around targeted gene therapy for cancer treatment, it also has various limitations, such as a lack of availability of related technology, high cost of the involved procedures, and ethical issues. This article will provide a review on the potentials and challenges of gene therapy targeting p53 and KRAS for the treatment of CRC.     

IDH Inhibitors and Immunotherapy for Biliary Tract Cancer: A Marriage of Convenience?

Systemic treatments have traditionally reported limited efficacy for biliary tract cancer (BTC), and although targeted therapies and immune checkpoint inhibitors have been found to play an increasingly important role in treatment, several questions remain unanswered, including the identification of biomarkers of response. The tumor microenvironment (TME) has recently attracted the attention of the BTC medical community, and is currently being studied due to its potential role in modulating response and resistance to systemic therapies, including immunotherapy. In this perspective article, we discuss available evidence regarding the interplay between TME, IDH inhibitors, and immunotherapy, providing rationale for the design of future clinical trials.     

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.     

Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review

Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.     

Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.     

Exosomes in the Treatment of Pancreatic Cancer: A Moonshot to PDAC Treatment?

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains a vast array of biomolecules, such as proteins and microRNAs. It is currently established that their role as messengers is central to a plethora of both physiologic and pathologic processes. Accumulating data have shed light on their contributions to carcinogenesis, metastasis, and immunological response. Meanwhile, the advancement of personalized targeted therapies into everyday clinical practice necessitates the development of cost-efficient treatment approaches. The role of exosomes is currently being extensively investigated towards this direction. This review aims to summarize the current pre-clinical and clinical evidence regarding the effects of exosomal applications in the timely diagnosis, prognosis, and therapeutic management of pancreatic cancer.