Biochimica et Biophysica Acta (BBA)

Achalasia and associated esophageal cancer risk: What lessons can we learn from the molecular analysis of Barrett's–associated adenocarcinoma? Publication date: Available online 4 May 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): K. Nesteruk, M.C.W. Spaander, I. Leeuwenburgh, M.P. Peppelenbosch, G.M. Fuhler Abstract Idiopathic achalasia and Barrett's esophagus (BE) are preneoplastic conditions of the esophagus. BE increases the risk of esophageal adenocarcinoma (EAC), while achalasia is associated with both EAC and esophageal squamous cell carcinoma (ESCC). However, while the molecular mechanisms underlying the transformation of esophageal epithelial cells in BE are relatively well characterized, less is known regarding these processes in achalasia. Nevertheless, both conditions are associated with chronic inflammation and BE can occur in achalasia patients, and it is likely that similar processes underlie cancer risk in both diseases. The present review will discuss possible lessons that we can learn from the molecular analysis of BE for the study of achalasia-associated cancer and contrast findings in BE with those in achalasia. First, we will describe cellular fate during development of BE, EAC, and ESCC, and consider the inflammatory status of the epithelial barrier in BE and achalasia in terms of its contribution to carcinogenesis. Next, we will summarize current data on genetic alterations and molecular pathways involved in these processes. Lastly, the plausible role of the microbiota in achalasia-associated carcinogenesis and its contribution to abnormal lower esophageal sphincter (LES) functioning, the maintenance of chronic inflammatory status and influence on the esophageal mucosa through carcinogenic by-products, will be discussed.

The role of inflammatory programmed cell death in gastrointestinal cancer and immune responses to intestinal microbial infection Publication date: Available online 3 May 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): Cheng-Bei Zhou, Jing-Yuan Fang Abstract Inflammatory programmed cell death, also called pyroptosis, is mediated by multiple inflammasomes which can recognize danger signals and activate the secretion of pro-inflammatory cytokines like IL-181 and IL-1β.2 It can induce cancer cell death within the gastrointestinal tract. NLRs,3 AIM2,4 GSDM5 family play important roles in pyroptosis signaling pathways in intestinal cancer such as gastric cancer, colitis-associated colorectal cancer and esophageal cancer, etc. Furthermore, several inflammasomes are elucidated to be involved in mucosal innate immune responses and modulate specific enteric pathogens infection. Precise modulation of inflammasome activation and exploration of potential diagnostic markers can contribute to the diagnosis, prevention and treatment of intestinal tumors and inflammatory or infectious disorders in human patients in the near future.

The AP-1 transcriptional complex: Local switch or remote command? Publication date: Available online 26 April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): Bejjani Fabienne, Evanno Emilie, Zibara Kazem, Piechaczyk Marc, Jariel-Encontre Isabelle Summary The ubiquitous family of AP-1 dimeric transcription complexes is involved in virtually all cellular and physiological functions. It is paramount for cells to reprogram gene expression in response to cues of many sorts and is involved in many tumorigenic processes. How AP-1 controls gene transcription has largely remained elusive till recently. The advent of the "omics" technologies permitting genome-wide studies of transcription factors has however changed and improved our view of AP-1 mechanistical actions. If these studies confirm that AP-1 can sometimes act as a local transcriptional switch operating in the vicinity of transcription start sites (TSS), they strikingly indicate that AP-1 principally operates as a remote command binding to distal enhancers, placing chromatin architecture dynamics at the heart of its transcriptional actions. They also unveil novel constraints operating on AP-1, as well as novel mechanisms used to regulate gene expression via transcription-pioneering-, chromatin-remodeling- and chromatin accessibility maintenance effects.

The power of small changes: Comprehensive analyses of microbial dysbiosis in breast cancer Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Sheetal Parida, Dipali Sharma Abstract Disparate occurrence of breast cancer remains an intriguing question since only a subset of women with known risk factors develop cancer. Recent studies suggest an active role of local and distant microbiota in breast cancer initiation, progression, and overall prognosis. A dysbiotic microbiota predisposes the body to develop cancer by inducing genetic instability, initiating DNA damage and proliferation of the damaged progeny, eliciting favorable immune response, metabolic dysregulation and altered response to therapy. In this review, we present our analyses of the existing datasets and discuss the local dysbiosis observed in breast cancer patients and different aspects of breast carcinogenesis that can be potentially influenced by local breast microbiota. Striking differences between microbial community compositions in breast of cancer patients compared to healthy individuals were noted. Differences in microbiome were also apparent between benign and malignant disease and between nipple aspirate fluid of healthy individuals and breast survivors. We also discuss the identification of distinct bacterial, fungal, viral as well as parasite signatures for breast cancer. These microbes are capable of producing numerous secondary metabolites that can act as signaling mediators effecting breast cancer progression. We review how microbes potentially alter response to therapy affecting drug metabolism, pharmacokinetics, anti-tumor effects and toxicity. In conclusion, breast harbors a community of microbes that can communicate with the host cells inducing downstream signaling pathways and modulating various aspects of breast cancer growth and metastatic progression and an improved understanding of microbial dysbiosis can potentially reduce breast cancer risk and improve outcomes of breast cancer patients. The human microbiome, now referred to as, the "forgotten organ" contains a metagenome that is 100-fold more diverse compared to the human genome, thereby, is critically associated with human health [1,2]. With the revelations of the human microbiome project and advent of deep sequencing techniques, a plethora of information has been acquired in recent years. Body sites like stomach, bladder and lungs, once thought to be sterile, are now known to harbor millions of indigenous microbial species. Approximately 80% of the healthy microbiome consists of Firmicutes and Bacteroidetes accompanied by Verrucomicrobia, Actinobacteria, Proteobacteria, Tenericutes and Cyanobacteria [[2], [3], [4], [5], [6], [7]]. The role of microbiome in diabetes, obesity and even neurodegenerative diseases was greatly appreciated in the last decade [1,[7], [8], [9], [10], [11], [12], [13], [14]] and now it has been established that microbiome significantly contributes to many organ specific cancers [1,15,16].

Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway? Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Xiang-Nan Yu, Hong Chen, Tao-Tao Liu, Jian Wu, Ji-Min Zhu, Xi-Zhong Shen Abstract The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.

Atomic force microscopy-based cancer diagnosis by detecting cancer-specific biomolecules and cells Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Taeyun Kwon, Sundaram Gunasekaran, Kilho Eom Abstract Atomic force microscopy (AFM) has recently attracted much attention due to its ability to analyze biomolecular interactions and to detect certain biomolecules, which play a crucial role in disease expression. Despite recent studies reporting AFM imaging for the analyses of biomolecules, the application of AFM-based cancer-specific biomolecule/cell detection has remained largely underexplored, especially for the early diagnosis of cancer. In this paper, we review the recent attempts, including our efforts, to analyze and detect cancer-specific biomolecules and cancer cells. We particularly focus on two AFM-based cancer diagnosis techniques: (i) AFM imaging-based biomolecular and cellular detection, (ii) AFM cantilever-based biomolecular sensing and cell analysis. It is shown that AFM-based biomolecular detection has been applied for not only early diagnosing cancer, by measuring the minute amount of cancer-specific proteins, but also monitoring of cancer progression, by correlating the amount of cancer-specific proteins with the progression of cancer. In addition, AFM-based cell imaging and detection have been employed for diagnosing cancer, by detecting cancerous cells in tissue, as well as understanding cancer progression, by characterizing the dynamics of cancer cells. This review, therefore, highlights AFM-based biomolecule/cell detection, which will pave the way for developing a fast and point-of-care diagnostic system for biomedical applications.

Targeting PI3K signaling in cancer: Challenges and advances Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Maria Chiara De Santis, Federico Gulluni, Carlo Cosimo Campa, Miriam Martini, Emilio Hirsch Abstract The key role of phosphoinositide 3-kinase (PI3K) pathway in different cellular processes and several disorders, together with the presence of targetable proteins, opened the way to promising studies for the development of small molecule inhibitors. Despite the high expectation, the shift of PI3K inhibitors to the clinic met several limitations due to the emergence of dose-limiting, on-target adverse effects. In this review, we will summarize the main issues and recent advances in PI3K inhibitors clinical trials. The effort to develop isoform-specific inhibitors, together with novel therapeutic strategies aimed at reducing the toxicity and adverse effects, opened a new promising era for PI3K inhibitors. In addition, we will focus on the recent emergence of class II and III PI3K inhibitors, which helped to define their class I non-redundant role.

Recent advances in extracellular vesicle research for urological cancers: From technology to application Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Liang Dong, Richard C. Zieren, Yanqing Wang, Theo M. de Reijke, Wei Xue, Kenneth J. Pienta Abstract Urological malignancies, including prostate cancer, bladder cancer and kidney cancer, are major causes of morbidity and mortality worldwide. Because of the high incidence, diversity in biology, and especially direct interaction with urine, urological cancers are an important resource for both scientists and clinicians for novel diagnostic and therapeutic discovery. Extracellular vesicles (EVs) are lipid bilayer encapsulated particles released by cells into the extracellular space. Since EVs work as a safe way to transport important biological information through the whole body, they are now recognized as an important mechanism of cell–cell communication and have opened a new window for us to gain a better understanding of cancer biology, novel diagnostics, and therapeutic options. In recent years, numerous evolutions in EV technologies and novel biological and clinical findings continue to be reported in the research field of urological cancers. This comprehensive review aims to give an update of recent advances in EV technologies and summarize the state-of-the-art knowledge of EVs related to prostate cancer, bladder cancer and kidney cancer, particularly focusing on the potential of EV as biomarkers and their biological roles in promoting cancer and metastasis.

Pyruvate kinase M2: A multifarious enzyme in non-canonical localization to promote cancer progression Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Sajid Amin, Peng Yang, Zhuoyu Li Abstract Rewiring glucose metabolism, termed as Warburg effect or aerobic glycolysis, is a common signature of cancer cells to meet their high energetic and biosynthetic demands of rapid growth and proliferation. Pyruvate kinase M2 isoform (PKM2) is a key player in such metabolic reshuffle, which functions as a rate-limiting glycolytic enzyme in the cytosol of highly-proliferative cancer cells. During the recent decades, PKM2 has been extensively studied in non-canonical localizations such as nucleus, mitochondria, and extracellular secretion, and pertained to novel biological functions in tumor progression. Such functions of PKM2 open a new avenue for cancer researchers. This review summarizes up-to-date functions of PKM2 at various subcellular localizations of cancer cells and draws attention to the translocation of PKM2 from cytosol into the nucleus induced by posttranslational modifications. Moreover, PKM2 in tumor cells could have an important role in resistance acquisition processes against various chemotherapeutic drugs, which have raised a concern on PKM2 as a potential therapeutic target. Finally, we summarize the current status and future perspectives to improve the potential of PKM2 as a therapeutic target for the development of anticancer therapeutic strategies.

Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy Publication date: April 2019 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1871, Issue 2 Author(s): Mengqian Li, Lu Gan, Andrew Song, Jianxin Xue, You Lu Abstract The combination of programmed cell death 1/programmed cell death ligand 1 blockade and thoracic radiotherapy has become the new standard of care in the treatment of locally advanced non-small-cell lung cancer. The information regarding the pulmonary safety of such therapy remains limited to mostly retrospective studies and case reports with a small portion of data from prospective clinical trials. By analyzing the underlying mechanisms of interactions between radiation and immunotherapy from preclinical data and summarizing safety data from relevant clinical studies with pulmonary toxicity, we believe that longer and rigorous follow-up is warranted, to determine if the combination of such modalities is appropriate for patients without risking undue toxicity.