Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year, from April 10-15 and May 17-21, 2021.
Oncotarget participating in the Annual AACR Meeting 2021 #AACR
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The American Association for Cancer Research (AACR) organizes an annual meeting program covering some of the most recent discoveries in cancer research. The conference aims to highlight work from the best minds in research and medicine from institutions all over the world. Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year.
As of June 2020, Scopus released their latest 2019 Journal Rankings on Oncology. Oncotarget is among their highest rated (Q1) journals and ranked number one in total citations in oncology. The journal has published outstanding papers and reviews by authors including Bert Vogelstein, Peter K. Vogt, Pier Paolo Pandolfi, Arnold J. Levine, Brian Druker, and Carol Prives. Founding Oncotarget Editorial Board members include Nobel Laureates Andrew V. Schally and Gregg L. Semenza; Lasker Award recipients Alexander Varshavsky, Brian J. Druker, and Gregg L. Semenza; and 16 members of the US National Academy of Sciences. Oncotarget is indexed and archived in PubMed, PubMed Central, Scopus, EMBASE, and META (Chan Zuckerberg Initiative) .
The 2021 AACR conference, a two-week online event, will take place from April 10-15 and May 17-21, 2021. Topics include population science and prevention, cancer biology, translational and clinical studies, survivorship, and advocacy.
In 2019, Oncotarget participated in the AACR Annual Meeting at the Georgia World Congress Center in Atlanta, Georgia, USA, and “AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics,” at the Hynes Convention Center in Boston, Massachusetts, USA. The total registration count from the 2019 AACR Annual Meeting was over 21,000—nearly 16,000 of which were scientific attendees from all over the world. Click here to view photos from Oncotarget’s participation in the 2019 AACR Annual Meeting.
Follow the Oncotarget Twitter account (@Oncotarget) for live updates about the conference using the #AACR21 hashtag.
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Researchers conducted a 2021 study to better characterize phyllodes tumors and other breast fibroepithelial lesions in order to improve diagnosis and treatment for patients.
Photomicrograph showing histology of a benign phyllodes tumor of the breast, from sections of an excision specimen (lumpectomy).
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Thankfully, around 80% of lumps found in human breasts turn out to be benign, or indolent, fibroadenoma (FAD). FADs fall into a category of breast fibroepithelial lesions (FELs), which include many heterogeneous pathological tumors, ranging from benign FADs to rare and potentially aggressive phyllodes tumors (PTs). After examination by a physician, these FELs may be diagnosed as either benign, borderline, or malignant.
“The current grading system remains unreliable in differentiating these tumors due to histological heterogeneity and lack of appropriate markers to monitor the sudden and unpredictable malignant transformation of PTs.”
The Study
To begin identifying the differentially expressed genes and proteins among FADs and PTs in benign, borderline, and malignant states, the researchers conducted quantitative global proteomics on Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections. They conducted a principal component analysis of the protein expression matrix to identify the overlapping proteomic profiles among FELs.
“Interestingly, we observed FADs and benign PTs clustered together compared to borderline and malignant ones, albeit with overlapping protein expression profiles.”
When FADs were compared with benign PTs, the researchers identified 32 proteins in FAD that were differentially regulated. The researchers elucidated many important distinctions between benign, borderline, and malignant FADs and PTs, and identified at least three potential prognostic markers that may aid in patient diagnosis and treatment. The progression of PTs from borderline to malignant and their mechanistic framework was clearly explained by the researchers in this study.
“The presence of extensive ECM proteins and EMT markers led us to hypothesize a model of deposition and degradation of these proteins thus triggering ECM remodeling and EMT acquisition in borderline PTs leading to its malignant state. Enrichment of platelet degranulation factors in malignant PT indicates active angiogenesis during this transformation.”
The Study
“Herein, our initial findings suggest that MUCL1, HTRA1, and VEGFD can be used as potential proteomic markers that could augment existing diagnosis, and help in monitoring the progression of the disease.”
Additional characterization of FELs using different omics platforms was recommended by the researchers to help better understand and manage the dynamics of PTs and malignant breast tumors.
“The present work shed light on a brief mechanistic framework of PTs aggressive nature and present potential biomarkers to differentiate overlapping FELs that would be of practical utility in augmenting existing diagnosis and disease management for this rare tumor.”
Click here to read the full scientific study, published in Oncotarget.
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Young people living in the Andes Mountains are disproportionately affected by hepatocellular carcinoma compared to other youth around the world. Researchers conducted a study to better understand the cause.
Peru. View of the Urubamba River through the Aguascalientes Village.
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Andean people live in sparsely populated regions in the Andes Mountains of South America. It is the longest mountain range in the world; spanning seven countries from southern Peru to southern Argentina. Due to the high elevations (averaging 13,000 feet; peaking at 22,834 feet), these areas are known for such low oxygen levels that Andean people have adapted physiologically to the extreme conditions.
Around the world, hepatocellular carcinoma (HCC) is the main form of primary liver cancer and commonly affects older patients after they have had prolonged liver disease. However, among Andean people, half of the total patients who develop HCC are adolescents and young adults. Researchers—from Sorbonne Université, Institut Pasteur, Université de Rennes, and Université de Toulouse in France, and the Instituto Nacional de Enfermedades Neoplásicas in Peru—conducted a study to better understand HCC in Andean people.
“To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults.”
The Study
“The 74 Peruvian patients with HCC included in the present study carried mitochondrial DNA (mtDNA) haplotypes of the four ancestral lineages (A–D) shared by Indigenous American populations (Figure 1A and Table 1) [23].”
The researchers retrospectively conducted transcriptome profiling of patient samples from 74 Peruvian patients with HCC. They compared gene expression data (after batch-effect removal) and found that Peruvian HCC is characterized as a distinct molecular subtype. This, now referred to as the “Amerind signature,” identifies Peruvian HCC as a distinct phenotypic cluster.
“A 961 gene signature was defined (hereinafter referred to as “Amerind signature”), of which 806 were upregulated and 155 downregulated in Peruvian HCC (Figure 3A and Supplementary Table 4).”
Methylome profiling was also conducted by the researchers to show the dynamics of DNA methylation marks, which revealed that Peruvian HCC is associated with a genome-wide hypermethylation pattern. They explain that DNA hydroxymethylation also represents a relevant epigenetic mark in Peruvian HCC. In addition, the researchers found evidence that Peruvian HCC tumor cells have a weaker retinoid signaling signature, which opens the door to potential therapeutic targets.
“The genomic analysis of Peruvian HCC evidenced a weaker retinoid signaling signature in tumor cells, which could pinpoint novel targets and drugs for anticancer targeted therapy (Figure 1C and Supplementary Table 1) [45]. We hypothesized that this weaker retinoid signaling could be responsible for the increased proliferation; hence, the pharmacological response to RA should antagonize this process.”
Conclusion
After comparing this sample of patients with Peruvian HCC with other HCC tumors from other countries around the world, molecular divergence in Peruvian HCC was demonstrated by showing “hierarchical clustering relying on a large and meaningful gene expression signature.” The researchers do not yet know if these differences are due to external/geographic or genomic factors.
“Whether this molecular phenotype is due to anthropological specificities embedded in genome architecture, to extrinsic etiological cues, or to subtle interplays between both components remains to be ascertained.”
With this being said, the researchers believe that this study stresses the need to carefully consider the potentially prominent roles of human genomic architecture and biogeography when it comes to cancer and underreported minorities and Indigenous patients, especially in low- and middle-income countries. They are forthcoming about limitations in their study and mention having analyzed a fairly small sized cohort. Importantly, the findings from this study create a case for developing therapeutics that are tailored to this new molecular subtype of HCC.
“The present study establishes a foundation for the dissection of the functional importance of RA-mediated epigenetic control in HCC and therapeutics tailored to patients with Indigenous American ancestry.”
Click here to read the full scientific study, published in Oncotarget.
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Researchers use a computer simulated modeling system to highlight the strengths and weaknesses of two ALK inhibitors.
Figure 2: Overview of brigatinib’s and alectinib’s mechanisms of action.
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Despite many therapeutic advances over the years, over half of patients with lung cancer die within one year of diagnosis. Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer, and around 3–7% of patients with NSCLC present with a rearranged ALK gene (ALK+). This abnormality produces aberrant ALK protein cell signaling pathway activity and causes cancer cells to grow and metastasize. ALK+ NSCLC patients often develop drug resistance to available ALK inhibitor drugs.
“Consequently, it is of the upmost importance to adequately use the currently available treatments in the correct order to maximize the life span of NSCLC patients.”
The researchers first began their study by characterizing the pathophysiology of ALK+ NSCLC after completing a detailed review of review papers published in PubMed between 2013 and 2018.
“To carefully characterize the pathophysiology of ALK+ NSCLC, we conducted an extensive and detailed full-length review of relevant review articles over the last 5 years in the PubMed database (from December 3rd 2013 to December 3rd 2018)[…]”
Next, to compare the strengths and weaknesses of two second generation ALK inhibitor drugs, brigatinib and alectinib, the researchers used a computer simulated modeling system—in silico. They explain that an in silico method of study can be highly useful when analyzing drug characteristics and predicting the biochemical characteristics and drug mechanisms of action.
“Overall, these systems can be employed for the exploration of anticancer drug mechanisms of action and their efficacy in specific patient profiles.”
The in silico system they used is called a Therapeutic Performance Mapping System (TPMS) and is based on artificial intelligence and pattern recognition models. This TPMS system was “trained” by the researchers in this study and given up-to-date biological and clinical data to input into its configuration. The mathematical models used to obtain the ALK inhibitors’ mechanisms of action were generated following the same methodology as described in this study.
“This methodology integrates available biological, pharmacological and medical information to generate mathematical models that simulate the mechanisms of action of drugs in a pathophysiological human context (Figure 4).”
To detect and explain the biological relationships that occur, the team used two distinct modeling methods: artificial neural networks and sampling-based methods. They applied Sobol sensibility analysis over the TPMS mathematical models in order to account for the impact of any noise affecting the final mechanisms of action. The researchers also performed drug-(patho)physiology motive relation finding and evaluated the impact of potential resistances and drug interferences over the mechanisms of action.
Results & Conclusion
“According to the current knowledge and the data herein presented, brigatinib might be more prone to present relevant metabolic and mechanistic interactions with other drugs than alectinib, which might be a safer option in poly-treated patients.”
“Brigatinib appears to have a wider mechanism of action, presenting targets that potentially act more strongly in most of the ALK+ NSCLC pathophysiological pathways, including invasiveness to the CNS [central nervous system].”
“On the other side, alectinib-induced RET inhibition might contribute to reducing the tumour immune evasion mechanisms.”
The researchers found that both drugs are known to be well-tolerated and show similar efficacy for the treatment of ALK+ NSCLC in a first-line setting. However, they explain that the differences in their characteristics shown in this study might allow for administration in more targeted patient populations that might see benefits from either brigatinib or alectinib. This deeper classification may also help when considering potential safety concerns in specific patient subpopulations.
“Future clinical studies will be needed to confirm these findings. The used approach can be applied for the evaluation of other next-generation ALKi, even if not yet approved, or exploring other questions, such as optimal treatment sequence.”
Click here to read the full scientific study, published in Oncotarget.
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Authors of this review paper discuss the complex crosstalk between cancer stem cells and macrophages, and potential anti-cancer strategies for future studies.
Figure 1: Main roles of tumor associated macrophages in cancer development and maintenance.
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“The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies,” Dr. Beatrice Aramini said, a thoracic surgeon and scientist from the University Hospital of Modena Reggio Emilia.
There have been numerous studies published over recent decades in an effort to understand the molecular mediators of cancer stem cells (CSCs) and tumor associated macrophages (TAMs). Several studies have contributed to bringing light to some of the complex crosstalk that occurs between these two cell types and within the tumor microenvironment. The authors of this review paper reference hundreds of studies and offer a thorough audit and analysis of the current state of this research.
About the Writers of the Review Article
“I mainly focus on lung cancer,” Dr. Aramini said. “I started this project about cancer stem cells in lung cancer since 2017, at University Hospital of Modena Reggio Emilia, joining the laboratory of cell therapies directed by Professor Massimo Dominici with the chief of medical oncology at University Hospital in Modena.”
Dr. Valentina Masciale, co-author, is a research fellow at the University Hospital of Modena Reggio Emilia. Dr. Masciale’s professional experience began by studying missing stroma cells. She then studied stem cells in regenerative medicine and currently she is working with Dr. Aramini on a project focused on lung cancer stem cells. The paper they wrote was revised and approved by seven other contributing authors.
“In this review, we describe the importance of cancer stem cells as the key drivers of cancer initiation and progression due to their unlimited cell renewal capacity and their ability to induce tumor formation,” Dr. Aramini said.
Introduction to Cancer Stem Cells
“Cancer stem cells (CSCs) constitute a cancer cell subpopulation similar to the other stem cell types in terms of self-renewal and multilineage differentiation potential but drive tumor development besides heterogeneity and dissemination of cancer cells [1–9].”
In 1997, Bonnet and Dick were the first researchers to report the existence of cancer stem cells in the tumor, in acute myeloid leukaemia. Since then, however, a standard marker to identify CSCs still has yet to be found.
“One of the main obstacles to proving the CSC model is the difficulty in identification and isolation of these cells [7, 33, 91].”
The authors explain that one of the problems with finding a marker such as this is that many markers found are not only able to detect CSCs, but they also detect non-tumor cells. This represents a major obstacle when developing new therapies to target CSCs only. The authors note that recently there have been several gene markers described by researchers for CSCs in different tumors, including brain, breast, blood, and lung.
“Indeed, there are currently no markers able to distinguish between stem cells and CSCs. Thus far, the best markers identified are those of onco-fetal stem cells, which are absent in adult organs and present in cancer cells [45–48].”
Theories About the Role of Cancer Stem Cells
This review refers to a few theories about the role of CSCs in cancer progression. One theory is based on the premise that tumor tissue is hierarchically organized into different types of cells, with the CSC subpopulation as the top of this hierarchy. In this theory, the other levels consist of additional differentiated tumor cells or cells with a limited proliferative potential. The “clonal evolution theory” hypothesizes that a rampant mutating cell is the catalyst for tumor progression.
“Peter Nowell was the first to describe the ‘clonal evolution theory,’ defining cancer as a complex process resulting from the development of a single out-of-control cell with multiple cell mutations that result in the progression of the tumor, which is kept viable through the selection of the most aggressive clones [89].”
Since the discovery of CSC plasticity and the possibility of switching from stem to non-stem cells, researchers have gained a more complex picture of the origin of tumor heterogeneity and more theories about the role of cancer stem cells in tumor progression.
“An opposing theory is based on the concept that CSCs are a group of cells endowed with a high self-renewal capacity that can set different phenotypes of tumorigenic cells [18, 88].”
Cancer Stem Cells and Macrophages
The researchers explain that macrophages are large specialized phagocytic cells that exist in tissues or at infection sites which act as part of the immune system. Arising from the bone marrow, macrophages perform multiple functions and roles in normal and tumor microenvironments, including pro-inflammatory activities and anti-inflammatory processes. Tumor-associated macrophages (TAM) comprise up to 50% of the tumor mass and have a close relationship with CSCs.
“The rising interest on these type of cells comes from recent study demonstrating that high number of tumor-associated macrophages correlate with the poor clinical prognosis in many solid tumors, including lung cancer, which is the field of our research group at the University Hospital of Modena,” Dr. Masciale said. “Another important aspect is the protective role of the tumor-associated macrophages play on tumors undergoing chemotherapy, which may impact the chemotherapy resistance and consequent tumor relapse.”
In recent studies, high numbers of TAMs in lung tumors, gastric cancer, and other cancer types, have been shown to correlate with a poor clinical prognosis. Macrophages are recruited to the tumor and, through crosstalk, provide protection to the tumor, contribute to immunosuppression in the tumor microenvironment and, eventually, drug resistance.
“The primary cause of failure in cancer treatment is the emergence of drug resistance that promotes the tumor spreading,” Dr. Masciale said.
“Cross-talk between CSCs and TAMs involves the recruitment of TAMs through vascularization and the release of chemokines by TAMs to preserve the quiescence of CSCs and modification of their antigens to escape from recruitment by immune cells.”
Future Perspectives
“Although most TAM-targeting strategies are in the pre-clinical stages, several factors used for TAMs depletion have already been tested in clinical trials [271, 272].”
Current efforts are underway to reprogram or inhibit the tumor-protective properties of tumor associated macrophages. Researchers are also investigating potential strategies to increase the efficacy of chemotherapy through nano-drug delivery to TAMs.
“Due to the significance of the tasks in which TAMs are involved, TAMs are increasingly becoming principal targets of novel therapeutic approaches, especially in the field of nanomedicine.”
The authors believe that targeting TAMs could trigger various reactions in the tumor, which are difficult to predict even given the individual variability from patient to patient. They also explain that targeting TAMs with CSCs offers another potential for treating different tumors to better control cancer progression and avoid tumor dissemination.
“In summary, generating new information about the interaction between TAMs and CSCs will be one of the most important challenges for the development of more effective targeted cancer therapies.”
Click here to read or watch an interview with the authors Behind the Study.
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Researchers in this study employed one of the few available murine cachexia models and validated its ability to be used in future studies of cancer-derived myocardial damage.
Part of Figure 2: Alterations in the myocardium of CT26-inoculated BALB/c mice.
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Cachexia, a complex metabolic syndrome characterized in part by the loss of muscle mass, can account for up to 30% of all cancer-related deaths. Myocardial atrophy, or cardiac remodeling/degradation, is a phenotype of cachexia and a common cause of death.
“The causes of cancer-derived myocardial impairment might be the effects of cancer itself, background heart disease, and influence of cancer treatments; however, they have not been given much clinical importance, and specific treatment efforts are delayed [8].”
Researchers from Nara Medical University, Hanna Central Hospital, and Hoshida Minami Hospital in Nara and Osaka, Japan, and Nantong University in Jiangsu Province, China, note that while myocardial damage in cancer patients is known to be a cause of death, there are few murine cachexia models available to evaluate cancer-derived heart disorders. Thus, there is a need for further studies that may allow researchers to establish an intervention to prevent myocardial damage in cancer patients.
“In this study, we used the mouse cancer cachexia model that we previously established [14] to examine the status of cancer-derived myocardial impairment reported in literature, and validate our model for studying cancer-derived myocardial impairment.”
The Study
Some causes of cancer-derived myocardial impairment have been reported as cancer-induced cytokines, oxidative stress, depletion of antioxidants, and protein catabolism as a result of AKT/mTOR inhibition.
“Despite these advances in our understanding, the multifactorial mechanisms underlying cancer-derived myocardial impairment remain incompletely understood, necessitating further investigations to elucidate the molecular mechanisms and prevent myocardial damage in cancer patients.”
The researchers previously established a mouse cancer cachexia model. In this study, they aimed to validate their model by employing it in the examination of cancer-derived myocardial impairment that has been reported in previous literature. Their study enlisted the mouse model, CT26 colon cancer cell cultures, protein extraction, histological analysis, immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), mitochondrial stress tests (Seahorse assay), glycolytic stress tests, and statistical analysis.
Conclusion
“In summary, our established mouse cachexia model showed various myocardial changes associated with cancer cachexia such as oxidative stress in the myocardium, energy metabolism, autophagy, and inflammatory cytokines.”
Results obtained by the researchers in this study using their mouse cachexia model are congruent with previously reported results about cancerous myocardial damage, and therefore provide reasonable evidence that it may be used in future studies.
“The established mouse cachexia model can therefore be considered useful for analyzing cancer-derived myocardial damage.”
Click here to read the full scientific study, published in Oncotarget.
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Different imaging and assessment tools across multiple clinics can result in varied prognostic values. Researchers from Japan conducted a retrospective study of harmonized pretreatment volume-based quantitative FDG-PET/CT parameters for prognostic values in breast cancer patients.
PET Scan image of whole body Comparision Axial, Coronal plane in patient breast cancer recurrence treatment.
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Breast cancer consists of a wide variety of tumor types, symptoms, disease progression courses, and responses to treatments. In the clinic, researchers decide which disease interventions to use by evaluating the patients’ stage of tumor-node-metastasis (TNM), histologic tumor grade, and the levels of hormone receptors and molecular markers that are present.
Standardized uptake value (SUV), metabolic tumor volume (MTV), and tumor lesion glycolysis (TLG) are derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). These variables have also been reported to correlate with clinicopathological prognostic factors and are considered predictive factors of prognosis.
Breast Cancer Prognostic Parameters
“Recently, noninvasive diagnostic tools have been gaining popularity for prediction of tumor behavior, with magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) with magnetic resonance imaging (MRI) reported to provide surrogate imaging biomarkers showing correlations with clinicopathological prognostic factors [2, 3].”
In a multi-institutional retrospective study in Japan, researchers—from the Hyogo College of Medicine, Nippon Medical School Hospital, National Cancer Center Hospital, Kinki University Faculty of Medicine, and Gunma Prefectural College of Health Sciences—explain that the factors and algorithms used by different assessment tools across multiple clinics can result in varied standardized uptake values. These inconsistencies have provided an opportunity for the researchers to standardize parameters of prognostic values when imaging breast cancer patients to improve patient outcomes.
“Thus, a harmonization strategy is necessary for comparing semi-quantitative PET parameters among available imaging methods, which is a notably relevant issue for multicenter trials employing different PET systems.”
The Study
Researchers gathered records of 546 patients treated from 2010 to 2016 with stage I–III invasive breast cancer. Of those patients, 344 were estrogen receptor (ER)-positive/human epidermal growth factor receptor two (HER2)-negative, 110 were HER2-positive, and 92 were triple-negative. The patients were treated at four separate institutions using different PET/CT scanner systems. In addition to surgeries, chemotherapy, and radiotherapy, patients were assessed during their follow-up appointments.
“Mammography, ultrasound, CT, bone scanning, and FDG-PET/CT were used for determining disease recurrence, metastasis, and progression during follow-up.”
Researchers in this study retrospectively performed histological and statistical analyses of overall survival and recurrence-free survival in patients of each breast cancer subtype group.
“An experienced reader (12 years of experience with oncologic FDG-PET/CT) who had no knowledge of other imaging results or clinical and histopathologic data retrospectively reviewed all of the FDG-PET/CT images.”
They found that the average maximum standardized uptake values (SUVmax) for HER2-positive and triple-negative tumor patients were higher than in patients with ER-positive/HER2-negative tumors.
“Harmonized primary tumor and nodal maximum SUVmax, metabolic tumor volume (MTV), and TLG indicated in pretreatment FDG-PET/CT results were analyzed.”
Conclusion
Results from this study suggest that harmonized PET classifications with final clinical response assessments demonstrate a better ability to predict disease-free survival compared to non-harmonized PET classification.
“We concluded that harmonized quantitative volume-based values, especially those for the primary tumor and nodal SUVmax and TLG, obtained with FDG-PET/CT can provide useful information regarding prognosis for both recurrence and death in patients with operable invasive breast cancer, including all three main subtypes. The findings presented here are considered useful for improving care of individual patients.”
Click here to read the full retrospective study, published in Oncotarget.
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Researchers review different varieties of cannabinoids, the signaling pathways they affect, and their role in different types of cancer.
Close up of female Cannabis flower with a high production of cannabinoid resin
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In a high-rated paper published in 2014 in Oncotarget, researchers from India’s Sanjay Gandhi Post Graduate Institute of Medical Sciences and the United States’ Ohio State University reviewed cannabinoids, their role in different types of cancer, and the signaling pathways they affect. Today, this paper currently presents with an Altmetric Attention score of 200.
“In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.”
Cannabinoids and Receptors
“[The] Cannabis sativa plant has been used for several hundreds of years both recreationally and medicinally.”
Researchers trace the earliest archaeological evidence of cannabis medical use back to ancient China, during the Han Dynasty. The use of this plant was recommended for rheumatic pain, constipation, disorders of the female reproductive tract, and malaria, among other conditions. Cannabis sativa contains three major classes of bioactive molecules; flavonoids, terpenoids, and 100+ types of cannabinoids.
Cannabinoids are a family of complex chemicals that activate and bind to two receptors in mammals named central cannabinoid receptor one (CB1) and peripheral cannabinoid receptor two (CB2). These receptors are found abundantly throughout the central nervous system and immune system.
“CB1/2 receptors are also responsible for proliferation, motility, invasion, adhesion and apoptosis of cancer cells both in vitro and in vivo.”
CB1 and CB2 receptors have been used as targets for the treatment of various diseases, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease, neuropathic and inflammatory pain, glaucoma, multiple sclerosis, cardiovascular disorders, obesity, and more. Today, in addition to inhibiting nausea and emesis, stimulating appetite, improving mood, and relieving pain and insomnia that cancer patients face, cannabinoids used in the targeted killing of tumor cells has been a major discovery in cancer treatment.
“In this review article we focused on the role of cannabinoids in different cancer types and the respective signaling pathways.”
Endocannabinoids
“Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors.”
Endocannabinoids act primarily as neuromodulators, or reverse messengers, which can affect the release of neurotransmitters. They also play important role in regulating inflammation, insulin, and fat and energy metabolism, which affects our mood, appetite, pain sensation, inflammation response, and memory.
Phytocannabinoids
“Phytocannabinoids are only known to occur naturally in significant quantities in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes.”
Over 120 phytocannabinoids are capable of interacting within the body’s own biological systems because their structures and behaviors mimic those of endocannabinoids (cannabinoids that are synthesized by our own bodies). The most prevalent natural cannabinoids are delta-9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), and cannabinol (CBN).
Synthetic Cannabinoids
“Synthetic cannabinoids are classified on the basis of chemical structure of molecules and they are capable of a more selective activation of cannabinoid receptors [28].”
The researchers explain that synthetic cannabinoids have been used extensively in pharmacology to gain better insight about their action in order to evaluate the potential use of cannabinoids clinically.
Within the synthetic category, classical cannabinoids are compounds isolated from the Cannabis sativa plant or its synthetic analogs. Nonclassical cannabinoids “are a family of AC-bicyclic and ACD-tricyclic cannabinoid analogs.” Aminoalkylindoles are non-cannabinoid molecules given cannabis-mimicking capabilities. Eicosanoids are compounds that can enhance or inhibit physiological and pathophysiological responses. These lipid mediators also have an affinity for CB1 and CB2 receptors.
Cannabinoids in Cancer
Multiple studies have shown that THC, CBD, and synthetic cannabinoids can inhibit breast cancer cell proliferation and drive them toward apoptosis.
“It [breast cancer] is classified into three main subtypes according to their molecular profiles: hormone receptor-positive, HER2-positive (ErbB2-positive, a member of EGFR family) and triple-negative tumors [42-43]. Cannabinoid-based medicines have been useful for the treatment of these three breast cancer subtypes.”
In prostate cancer, CB1 and CB2 expression levels are often higher in prostate cancer tissues and several cell lines compared to normal prostate epithelial cells. Studies have found that cannabinoids have either induced cell death or activated pathways that lead to growth inhibition and increased patient survival.
Preclinical cancer models have shown that cannabinoids can alter gene expression, block enzymes, inhibit signaling pathways, and induce apoptosis in mice with lung cancer. In skin and pancreatic cancers, researchers have found that the activation of CB1/2 receptors induced the apoptotic death of tumorigenic cells, without affecting the normal cells. In bone cancer studies, researchers found that cannabinoids reduced pain and bone loss in mice.
“Cannabinoids could halt tumor development without side effects via specific targeting of CB1/CB2 receptor.”
Cannabinoids have anti-tumorigenic properties in glioma, lymphoma, oral cancers, and thyroid carcinoma. In young people, marijuana smoking has been found to increase the incidence of head and neck cancer, however, cannabinoids have anti-tumor properties.
Conclusion
“Cannabinoids exert a direct anti-proliferative effect on tumors of different origin.”
Given that cannabinoid receptors are often demonstrated to be expressed higher in tumor cells than in normal cells, cannabinoids are more specific to cancer cells than to normal cells. The researchers conclude their review by noting that it is important to identify which cannabinoids are most compatible with an individual cancer or disorder to have the greatest impact on patient outcome.
“It is important to understand which of the cannabinoid receptors are expressed and activated in different tumors as each receptor follows a different signaling mechanism.”
Click here to read the full scientific review, published in Oncotarget.
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In search of new ways to target lung cancer cells, researchers in this study demonstrated that miR-708 has anti-tumorigenic properties.
Photomicrograph of fine needle aspiration (FNA) cytology of a pulmonary (lung) nodule showing adenocarcinoma, a type of non small cell carcinoma.
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Despite the innumerable biomedical advancements made in the detection, classification, and treatment of cancer since the 1971 National Cancer Act, lung cancer survival rates are still staggeringly low. In addition, every year over $12.1 billion is spent on lung cancer care in the United States. Non-small cell lung cancer (NSCLC) contributes to 85% of lung cancers and within this classification there are two main subtypes: adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).
“Although tumors are differentiated by subtype, LUAD and LUSC are generally treated with the same chemotherapeutics.”
Researchers, from the New Jersey Medical School’s academic health center, Rutgers Biomedical & Health Sciences, say that discovering new biomarkers that can help better distinguish between NSCLC subtypes is necessary to improve patient outcomes. In 2020, they conducted a study of a microRNA that is dysregulated in lung cancer, miR-708, to clarify its tumor suppressive or oncogenic functions within lung cancer cells.
“Lung cancer is a complex collection of deadly diseases that are generally hard to detect and treat. Therefore, it is crucial to develop novel methods to identify, distinguish, and treat lung cancer.”
The Study
The researchers in this study explain that it is crucial to take the entire tumor microenvironment (TME) into consideration when devising treatments for cancerous tumors. Historically, many chemotherapies that have been developed are successful in targeting tumors, but contribute to damaging the surrounding cells and tissues in the TME—contributing to harm and extending recovery time. In newer treatments being developed, researchers have considered the benefits of targeting the pro-tumor effects of particular immune cells and activating the immune system to attack cancer cells.
“miR-708 has previously been described as being both oncogenic and tumor suppressive in lung cancer [63–65]. Therefore, we aimed to clarify the tumor suppressive or oncogenic functions of miR-708 in lung cancer cells.”
This new potential microRNA with potent anti-tumorigenic effects for non-small cell lung cancer (NSCLC) was identified by the researchers. To determine the clinical relevance of miR-708 in lung cancer patients, the researchers analyzed data from The Cancer Genome Atlas (TCGA) using the TCGA-assembler 2 R software package. They used mammalian cell cultures to perform miRNA and 5-Azacytidine treatments, RNA isolation using TRIzol, quantitative real-time RT-PCR, western blot analysis, plasmids, luciferase reporter assays, Enzyme-Linked Immunosorbent Assay (ELISA) analysis, phenotypic assays; Water Soluble Tetrazolium Salts (WST)-1 assay; Ki-67 staining; Annexin V staining; Cell migration assay, and Bioinformatic and statistical analyses.
“We next examined expression of miR-708 in normal and lung cancer cells to determine if our cell lines faithfully replicated clinical data.”
Results
The researchers discovered miR-708 was underexpressed in lung cancer cells compared to normal lung cells. A lower expression of miR-708 correlated with decreased survival in patients with squamous cell carcinoma non-small cell lung cancer. They demonstrated that miR-708 suppressed the production of the pro-tumorigenic hormone called prostaglandin E2 (PGE2) (located in the arachidonic acid (AA) metabolic inflammatory pathway), by directly repressing the expression of COX-2 and mPGES-1 in lung cancer cells.
“We also demonstrated that miR-708 decreases lung cancer cell metabolism (Figure 5), proliferation (Figure 6), survival (Figure 7), and migration (Figure 8).”
Conclusion
The researchers were left with some outstanding questions about miR-708. First, they wondered why miR-708 expression is decreased in lung cancer cells compared to normal cells in the lungs. They suggest the cause may be the hypermethylation of the ODZ4 promoter region in lung cancer cells, a loss of tumor suppressive transcription factors, repressed CHOP activity, or specifically, the glucocorticoid receptor-alpha (GRα) repression of CHOP activity.
“Our work has identified novel tumor suppressive miR-708 functions by suppressing oncogenic PGE2 production through targeting of COX-2 and mPGES-1. These findings could be the foundation for identifying novel miR-708 targets, as well as regulators of miR-708 expression in cancer.”
“Moreover, our study highlights the need to better understand lung cancer biology to improve diagnosis and treatment of lung cancer, ultimately aiming to increase positive patient outcomes.”
Click here to read the full scientific study, published in Oncotarget.
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Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.
In his recent paper, Dr. Mikhail Blagosklonny explains his perspective on the current landscape of anti-aging drug studies, a key differentiation between healthspan and lifespan variables, and the next steps for human use of anti-aging drugs—beyond clinical trials.
Aging in humans seems as natural as aging in leaves—but is it necessary?
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The process of human aging is a fascinating mystery. Despite all that we do not know, a handful of researchers have dedicated recent decades to the exciting beginnings of solving this biological riddle. One such researcher is Dr. Mikhail Blagosklonny. As a professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, and Editor-in-Chief at the AgingandOncotarget journals, Dr. Blagosklonny’s mission is to prevent cancer (and other age-related diseases) by inhibiting the aging process—preventing cancer by maintaining youth.
The cover paper chosen for Oncotarget’s Volume 12, Issue #3, is titled, “The goal of geroscience is life extension;” a research perspective written by Dr. Blagosklonny. In this compelling paper, he reflects on the history of anti-aging studies, the differences between drugs that enhance healthspan versus lifespan, and next steps in the human application of anti-aging drugs.
Hyperfunction Theory of Aging
“According to the geroscience hypothesis, aging is a risk factor for diseases [127]. According to hyperfunction theory, in contrast, aging is a sum of all age-related diseases, not their risk factors.”
Dr. Blagosklonny defines aging as a continuation of human development, driven partially by growth-promoting pathways which drive age-related diseases—he has coined this as the hyperfunction theory.
“Hyperfunction (inappropriate activation) of these signaling pathways directly drive all age-related diseases, which are manifestations of aging. We just need clinically available inhibitors (drugs) of these signaling pathways to extend both healthspan and lifespan, by slowing aging.”
Increasing Lifespan via Increasing Healthspan
Before beginning his interpretation of data from previous anti-aging research studies, Dr. Blagosklonny emphasises the importance of correctly measuring healthspan and lifespan. As indicated in his paper title, the goal of geroscience is to extend lifespan by way of extending overall healthspan.
“Healthspan is a period of life without age-related diseases [27]. It is disease-free survival.”
Healthspan can be difficult to measure due to the nature and hidden course of many diseases. If one particular disease is subdued by treatment in a study and healthspan appears to be increased (through one marker of health or another), this does not guarantee that other age-related diseases have been nullified by this treatment. Dr. Blagosklonny explains that accurate measurements of healthspan are important because, based on the hyperfunction theory, aging is the sum of all age-related diseases.
“After all, aging is an exponential increase of death with age and should be measured by deadly diseases.”
Another point he makes is that many anti-aging drug trials have presented results finding increased healthspan in mice without demonstrating an increase in lifespan. Given that increased healthspan should always lead to increased lifespan, it is not sufficient to only measure healthspan without measuring lifespan in animal studies of anti-aging drugs. If lifespan is not increased, the drug does not demonstrate longevity or anti-aging properties.
“So how is it possible that some senolytics, NAD boosters and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health.”
Over the years, numerous initially promising anti-aging drugs have been tested and debunked by researchers. No compound has continued to withstand the many tests, or has delivered consistent results, quite like the unique bacterium, rapamycin.
Anti-aging Properties in Rapamycin
Rapamycin was discovered in 1964 in a test tube sample of dirt taken from Easter Island—a highly remote volcanic island in the Pacific ocean, west of Chile. Initially looking for antibiotics (often uncovered in the dirt) researchers found the rapamycin bacteria unexpectedly. To their surprise, this new bacteria created a defensive chemical with the ability to affect the activity of a protein and homeostatic ATP sensor called the mammalian target of rapamycin, or mTOR. mTOR is now known to function in regulatory pathways that are responsible for governing cell growth.
“It was predicted that rapamycin must extend lifespan before it was shown in any animal [105].”
In 1999, rapamycin was FDA approved to regulate hyperimmunity in transplant patients to help enable their immune system to accept a new organ. Since then, rapamycin’s ability to slow cell growth and proliferation has been widely accepted as an anticancer agent and the focus of anti-aging studies in a number of mouse-modeled trials.
“Since 2009, dozens of studies have shown that rapamycin extends medium and maximum lifespan in both males and females in all strains of normal mice tested, as well as in some cancer-prone and short-lived mice [36, 40–70].
Other Drugs With and Without Anti-aging Potential
In this paper, Dr. Blagosklonny categorizes a list of seemingly debunked anti-aging drugs with little or no results, including antioxidants, resveratrol, curcumin, quercetin (used alone), and spermidine. He explains that some of these drugs may have potential when used in combination with other drugs in future studies.
He acknowledges potential in berberine (one study found promising initial results), fisetin (clinically available and safe for human use), 17-alpha-estradiol (only results in male mice thus far), acarbose (blocks digestion of complex carbs), enalapril (decreases oxidative damage), losartan (angiotensin receptor blocker), quercetin with dasatinib (clinically available and safe for human use), and metformin.
“Some life-extending drugs are already approved for human use: supplements (fisetin, vitamin B3 and its analogs), over-the-counter medicine (aspirin) and prescription drugs (rapamycin, metformin, dasatinib, enilopril).”
Dr. Blagosklonny recalls a famous study of metformin where, at a low doses, it increased lifespan in male mice and, at high doses, it ironically decreased lifespan. Metformin was also tested with rapamycin in this study and demonstrated improved results in extending lifespan.
“Yet, a combination of metformin and rapamycin should be re-tested to include a rapamycin-alone group.”
Conclusion
“I expect that a combination of low doses of pan-mTOR and MEK inhibitors with high doses of rapamycin would extend life further compared with rapamycin alone. That could be the next important advance in the anti-aging field since the discovery of anti-aging properties of rapamycin.”
Dr. Blagosklonny believes that researchers should not wait for the lifespan results of clinical trials in humans to begin widespread application of these drugs, since studies already safely display increased lifespan and longevity in mouse models. He is so convinced by rapamycin that Dr. Blagosklonny is currently taking 10 milligrams of rapamycin per week along with his personalized treatment plan, a ketogenic diet, and exercise to jumpstart the next phase of human anti-aging trials within our lifetime. He notes that medical doctors interested in this topic may email Blagosklonny@rapalogs.com or follow him on Twitter @Blagosklonny.
“This article does not represent medical advice or recommendations to patients. The media should exercise caution and seek expert medical advice for interpretation when referring to this article.”
Oncotargetis a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.
