Diverse mechanisms of PARP inhibitor resistance in ovarian cancer Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Matthew John Wakefield, Ksenija Nesic, Olga Kondrashova, Clare L. Scott

The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: A systematic review and meta-analysis of randomized and non-randomized trials Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Omar Najim, Sofie Seghers, Laurine Sergoynne, Hélène Van Gaver, Konstantinos Papadimitriou, Kristien Wouters, Xuan Bich Trinh, Manon T. Huizing, Wiebren Tjalma Abstract Background Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy. Objective The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer. Methods A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors. Results The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%–31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28–26.62, P ≤.001). Conclusion ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.

Mechanisms of acquired tumor drug resistance Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Svetlana N. Aleksakhina, Aniruddh Kashyap, Evgeny N. Imyanitov Abstract Systemic therapy often results in the reduction of tumor size but rarely succeeds in eradicating all cancer cells. Drug efflux, persistence of cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and down-regulation of apoptosis are the most known general causes of therapy failure. Tumor escape from targeted compounds often involves pathway-specific mechanisms, which result in the restoration of the affected signaling cascade. The acquisition of drug resistance is mediated by mutations, changes in gene expression, alternative splicing, post-translational protein modifications, etc. Development of resistance to therapy may not necessary involve the emergence of new tumor clones: multiple studies demonstrate that even chemonaive neoplasms already have a small population of cells, which are capable of surviving therapeutic pressure and facilitating the disease progression. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of drug-resistant malignant lumps may help to prolong the time to treatment failure. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models. The development of approaches that allow efficient monitoring of the evolution of tumor phenotype in clinical setting presents a challenge.

The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Wu-Hu Zhang, Wen-Quan Wang, He-Li Gao, Xian-Jun Yu, Liang Liu Abstract Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.

From squamous intraepithelial lesions to cervical cancer: Circulating microRNAs as potential biomarkers in cervical carcinogenesis Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Fernanda Costa Brandão Berti, Amanda Salviano-Silva, Helen Cristina Beckert, Karen Brajão de Oliveira, Gabriel Adelman Cipolla, Danielle Malheiros Abstract Despite the essential role of Human Papillomavirus (HPV) in cervical carcinogenesis, other factors are required for cancer establishment, like miRNAs. Such molecules present a complex biogenesis, being diversely distributed across tissues and biological fluids, as cell-free miRNAs or miRNAs present in extracellular vesicles (EV). After HPV infection, an interplay between HPV and the miRNA network occurs in cervical cells. As the virus persists and cellular transformation occurs, specific patterns of miRNA expression are found in different stages of cervical disease. Thus, defining promising miRNAs/specific miRNA signatures - especially circulating miRNAs - represents an interesting strategy for screening (diagnosis, prognosis, etc.) those stages. Despite the limited number of studies investigating circulating miRNAs in distinct biological fluids, accumulating data have pointed to some promising candidates, both as cell-free or EV-derived miRNAs. Here we highlight some of these promising non-invasive biomarkers and bring attention to the urgent need for efforts in this field. Graphical abstract

Sodium homeostasis in the tumour microenvironment Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Theresa K. Leslie, Andrew D. James, Fulvio Zaccagna, James T. Grist, Surrin Deen, Aneurin Kennerley, Frank Riemer, Joshua D. Kaggie, Ferdia A. Gallagher, Fiona J. Gilbert, William J. Brackenbury Abstract The concentration of sodium ions (Na+) is raised in solid tumours and can be measured at the cellular, tissue and patient levels. At the cellular level, the Na+ gradient across the membrane powers the transport of H+ ions and essential nutrients for normal activity. The maintenance of the Na+ gradient requires a large proportion of the cell’s ATP. Na+ is a major contributor to the osmolarity of the tumour microenvironment, which affects cell volume and metabolism as well as immune function. Here, we review evidence indicating that Na+ handling is altered in tumours, explore our current understanding of the mechanisms that may underlie these alterations and consider the potential consequences for cancer progression. Dysregulated Na+ balance in tumours may open opportunities for new imaging biomarkers and re-purposing of drugs for treatment.

Microbial carcinogenesis: Lactic acid bacteria in gastric cancer Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Karla Vinasco, Hazel M. Mitchell, Nadeem O. Kaakoush, Natalia Castaño-Rodríguez Abstract While Helicobacter pylori is a fundamental risk factor, gastric cancer (GC) aetiology involves combined effects of microbial (both H. pylori and non-H. pylori), host and environmental factors. Significant differences exist between the gastric microbiome of those with gastritis, intestinal metaplasia and GC, suggesting that dysbiosis in the stomach is dynamic and correlates with progression to GC. Most notably, a consistent increase in abundance of lactic acid bacteria (LAB) has been observed in GC patients including Streptococcus, Lactobacillus, Bifidobacterium and Lactococcus. This review summarises how LAB can influence GC by a number of mechanisms that include supply of exogenous lactate —a fuel source for cancer cells that promotes inflammation, angiogenesis, metastasis, epithelial-mesenchymal transition and immune evasion—, production of reactive oxygen species and N-nitroso compounds, as well as anti-H. pylori properties that enable colonization by other non-H. pylori carcinogenic pathobionts.

Cell death in photodynamic therapy: From oxidative stress to anti-tumor immunity Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Claire Donohoe, Mathias O. Senge, Luís G. Arnaut, Lígia C. Gomes-da-Silva Abstract Photodynamic therapy is a promising approach for cancer treatment that relies on the administration of a photosensitizer followed by tumor illumination. The generated oxidative stress may activate multiple mechanisms of cell death which are counteracted by cells through adaptive stress responses that target homeostasis rescue. The present renaissance of PDT was leveraged by the acknowledgment that this therapy has an immediate impact locally, in the illumination volume, but that subsequently it may also elicit immune responses with systemic impact. The investigation of the mechanisms of cell death under the oxidative stress of PDT is of paramount importance to understand how the immune system is activated and, ultimately, to make PDT a more appealing/relevant therapeutic option.

Functional analysis of deubiquitylating enzymes in tumorigenesis and development Publication date: December 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1872, Issue 2 Author(s): Ji Cheng, Jianping Guo, Brian J. North, Bin Wang, Chun-Ping Cui, Hongchang Li, Kaixiong Tao, Lingqiang Zhang, Wenyi Wei Abstract Deubiquitylating enzymes (DUBs) are proteases that remove the ubiquitin moiety from ubiquitylated substrates to antagonize the modification mediated by E3 ubiquitin ligases. Currently, DUBs have been found to play critical roles in the regulation of various physiological or pathological processes, such as embryogenesis, immune homeostasis, tumorigenesis and neurodegenerative diseases. Accumulating evidences have suggested that different DUBs exert distinct function such as oncogenic, tumor-suppressive or context-dependent roles in tumorigenesis, mainly by affecting the protein stability, enzymatic activity or subcellular localization of its substrates. Importantly, multiple potent inhibitors targeting the enzymatic activity of oncogenic DUBs have been developed and show promising anti-cancer efficacy in preclinical models. Thus, exploring the unique role of DUB enzymes and their downstream effectors will provide novel insights into the molecular basis of cancer development. Here, we review and summarize recent progress on DUB functional annotation, as well as its biochemical regulation, to provide a better understanding for cancer therapies by targeting DUBs.

Challenges in liver cancer and possible treatment approaches Publication date: Available online 1 November 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): David Anwanwan, Santosh Kumar Singh, Shriti Singh, Varma Saikam, Rajesh Singh Abstract Globally, liver cancer is the most frequent fatal malignancy; in the United States, it ranks fifth. Patients are often diagnosed with liver cancer in advanced stages, contributing to its poor prognosis. Of all liver cancer cases, >90% are hepatocellular carcinomas (HCCs) for which chemotherapy and immunotherapy are the best options for therapy. For liver cancer patients, new treatment options are necessary. Use of natural compounds and/or nanotechnology may provide patients with better outcomes with lower systemic toxicity and fewer side effects. Improved treatments can lead to better prognoses. Finally, in this review, we present some of the problems and current treatment options contributing to the poor outcomes for patients with liver cancer.