Category: Oncotarget

Trending with Impact: Benign, Borderline, and Malignant Breast Tumors

March 19, 2021

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.

However, there is a need to improve accurate diagnosis and distinction between FELs using a marker-based diagnostic approach. In an effort to better characterize FELs, researchers from India’s CSIR-Centre for Cellular and Molecular Biology, Institute of Bioinformatics, Gandhi Hospital, Government Medical College, and Manipal Academy of Higher Education conducted a trending 2021 study, titled: “Quantitative proteome profiling stratifies fibroepithelial lesions of the breast.”

“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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Oncotarget

Trending with Impact: Hepatocellular Carcinoma in The Andes Mountains

March 11, 2021

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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Oncotarget

Trending with Impact: Machine Learning Used to Compare ALK Inhibitors

March 8, 2021

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.”

In 2021, researchers from Spain conducted a study published in Oncotarget, titled: “Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using an in silico systems biology-based approach.” This trending paper was authored by researchers practicing at the Hospital Germans Trias i Pujol, Takeda Farmacéutica España, Anaxomics Biotech, and Universitat Pompeu Fabra.

The Study

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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Oncotarget

Trending with Impact: Crosstalk In the Tumor Microenvironment

February 25, 2021

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. — **Figure 1:** Main roles of tumor associated macrophages in cancer development and maintenance.

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A review paper published by researchers from the University of Modena and Reggio Emilia in Italy and the Sulaiman AlRajhi Medical School in Saudi Arabia is trending and titled, “Cancer stem cells and macrophages: molecular connections and future perspectives against cancer.”

“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 the full scientific review, published in Oncotarget.

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Oncotarget

Trending with Impact: Murine Model of Cancer-derived Myocardial Damage

February 18, 2021

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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Oncotarget

Trending with Impact: New Prognostic Parameters for Breast Cancer

February 16, 2021

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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Oncotarget

An Overview of Cannabis and Cancer

February 9, 2021

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

The Top-Performer series highlights research literature published in Oncotarget that has generated a high Altmetric score. Altmetric scores, located at the top-left of trending Oncotarget papers, provide an at-a-glance indication of the volume and type of online attention the research has received. Read Oncotarget’s Top 100 Altmetric papers.

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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.”

Years after this paper was published, subsequent studies have confirmed and expanded on many ideas mentioned in this review, including the regenerative and pharmacological effects of THC, synthetic cannabis used to treat thrombosis, increased expression of CB2 potentially linked to colon cancer, experiments with cannabis extracts, synergistic combinations of cannabinoids, and much more.

Click here to read the full scientific review, published in Oncotarget.

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Oncotarget

Trending with Impact: Novel MicroRNA Underexpressed in Lung Cancer

February 4, 2021

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

Trending with Impact: New Plant Extracts Reveal Anti-aging Properties

January 29, 2021

In search of natural compounds with previously unknown geroprotective properties, researchers used a strain of budding yeast to test 53 plant extracts for their ability to impact the biology of aging and age-related diseases.

Scientist is sampling a chemical extract from organic natural, research and develop background. Scientific concept is sample project about herbal medicine.

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As we age, humans are subjected to a wide variety of age-related diseases, such as arthritis, diabetes, heart disease, kidney disease, liver dysfunction, sarcopenia, stroke, neurodegenerative diseases, and many forms of cancer.

Plant extracts have been consumed for hundreds of years in dietary customs and used as traditional herbal medicines in China and in the Mediterranean. Some of these plant extracts are classified by government health agencies, such as Health Canada, as not only safe for human consumption but also as health-improving supplements with clinically proven benefits to human health. Researchers hypothesized that some of these plant extracts (PEs) may have geroprotective properties. A geroprotector is any compound capable of modulating the root cause of aging and age-related diseases to prolong lifespan in modeled organisms and animals. A couple of well-known potential geroprotectors include melatonin and metformin.

In their previous 2016 study, researchers from Concordia University and Idunn Technologies—both located in Quebec, Canada—screened thirty-five plant extracts and identified 6 as capable of prolonging the length of time a cell can survive, or its chronological lifespan (CLS), and delaying chronological aging in the wild type strain of Saccharomyces cerevisiae budding yeast. On a mission to uncover a new set of plant extracts with geroprotectivity, these same researchers conducted a larger screening of plant extracts in a 2020 study.

“The objective of the present study was to search for previously unknown aging-delaying (geroprotective) PEs. To attain this objective, we conducted a new screen of many extracts from plants used in traditional Chinese and other herbal medicines or the Mediterranean and other diets.”

The Study

In this study, to learn more about new PEs and the mechanisms of aging and longevity, the researchers continued using the wild type strain of Saccharomyces cerevisiae budding yeast. They explained that S. cerevisiae has short and easily measurable replicative (number of times a cell can divide prior to senescence) and chronological lifespans, is completely sequenced, commercially available, and conducive to comprehensive molecular analyses.

Researchers tested 53 new plant extracts on chronologically aging S. cerevisiae budding yeast. The plant extracts were derived from fruits, berries, beans, herbs, flowers, roots, seeds, leaves, stems, whole plants, bulbs, buds, bark, skins, resin, aerial parts, mushroom bodies, and fermented rice.

“In a quest for previously unknown geroprotective natural chemicals, we used a robust cell viability assay to search for commercially available plant extracts that can substantially prolong the chronological lifespan of budding yeast.”

To determine geroprotectivity from these plant extracts, the researchers cultured, diluted, and fed the budding yeast with glucose. Then, after adding the new PEs, they performed a variety of tests and calculated measurements, including: chronological lifespan assay; oxygen consumption assay; plating assay; quantitative assay; fluorescence microscopy; measurements of the frequencies of spontaneous mutations; glucose concentration measurement assay; age-specific mortality rates; the Gompertz slope; the mortality rate coefficient; and mortality rate doubling time.

Results

“We discovered fifteen PEs that extend the longevity of chronologically aging budding yeast.”

The team was able to identify 15 new geroprotective PEs that have not previously been known for their ability to prolong the lifespan of yeast or other organisms. Based on the results of their measurements and assays, the researchers also identified the cellular processes that these PEs engaged in to prolong the yeast’s chronological lifespan.

“Our study provides evidence that each of the fifteen longevity-extending PEs satisfies all the criteria previously proposed for a CRM.”

CR stands for caloric restriction and CRM stands for caloric restriction mimetics. This means that these new PEs were found capable of mimicking the substantial anti-aging effects that calorie restriction has on organisms and animals, without a reduction in calorie intake.

“Each of the fifteen PEs extends the longevity of chronologically aging yeast under non-CR conditions on 2% (w/v) glucose significantly more efficiently than it does under CR conditions on 0.5% (w/v) glucose.”

They found that the PEs extended the longevity of chronologically aging yeast by decreasing the rate of aging, stimulating a hormetic stress response, intensifying mitochondrial respiration, altering the pattern of age-related changes in intracellular reactive oxygen species, and increasing cell resistance to long-term oxidative and thermal stresses.

“Each of the fifteen geroprotective PEs decreases the extent of age-related oxidative damage to cellular proteins, and many of them slow the aging-associated buildup of oxidatively impaired membrane lipids as well as mitochondrial and nuclear DNA.”

In addition to many more findings, the effects of 15 PEs were found to decrease the frequency of mitochondrial DNA mutations in rib2 and rib3 proteins under non-calorie restricted conditions in S. cerevisiae.

Conclusion

The 15 plant extracts in this study that were newly discovered as geroprotective are as follows: berry extract from a small palm commonly known as Saw Palmetto, extract of the aerial parts from a flowering plant commonly known as the St. John’s Wort, extract from the leaf of Yerba Mate, whole plant extract of Yerba Mate, extract from the leaf of Holy Basil Tulsi, extract from the herb of the perennial plant Solidago Virgaurea, Orange fruit extract, whole plant extract from the common Hop (used in beer), Grape skin extract, whole plant extract from the Green Chiretta, root extract from the perennial Goldenseal herb, Fenugreek seed extract, Barberry root bark extract, extract from the leaf, flower, and stem of the common Hawthorn, and leaf extract from the Red-seeded Dandelion.

“Therefore, we are interested in investigating how different combinations of the fifteen geroprotective PEs described here influence the extent of yeast chronological aging delay. We will be looking for the combinations of geroprotective PEs that exhibit synergistic or additive effects on the extent of yeast chronological aging delay.”

Click here to read the full scientific study, published in Oncotarget.

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Oncotarget

Trending with Impact: Bacterial Therapy Experiments in Prostate Cancer

January 21, 2021

Researchers reveal their positive findings from a study of bacterial cancer therapy using a strain of Salmonella typhimurium in mouse-modeled prostate cancer.

PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope. - Image — PC-3 human prostate cancer cells stained with blue Coomassie, under a differential interference contrast microscope.

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Over the past few decades, numerous studies have emerged using the promising strategy of bacteria as vehicles to deliver drugs or genes in tumor‐targeted therapies. Researchers say that bacterial cancer therapy may be able to overcome some of the limitations that conventional cancer therapy is stunted by, including the development of drug resistance.

Researchers in this study—from Yale University in Connecticut, the University of Missouri, the Harry S. Truman Memorial Veterans Hospital, and the Cancer Research Center in Missouri, and DeSales University in Pennsylvania, U.S.—used a Salmonella typhimurium strain (CRC2631) of bacteria (previously reported to have tumor-targeting capabilities) in prostate cancer-positive mouse-models and evaluated its toxicity, targeting ability, and genetic stability.

“Here, we report the toxicological and in vivo tumor-targeting profiles of CRC2631 in the syngeneic and autochthonous mouse model of aggressive prostate cancer, TRAMP (Transgenic Adenocarcinoma of Mouse Prostate).”

“The B6FVB TRAMP model recapitulates some of the key genetic aspects of human prostate cancer.”

The Study

“VNP20009 is considered as the safety benchmark in bacterial cancer therapy development because it has been safely administered in human cancer patients [7, 30].”

“To determine the safety profile of CRC2631, we performed CRC2631 and VNP20009 comparative toxicological studies in TRAMP animals.”

The team focused on measuring toxicity through treatment-related weight loss and lethality. Groups of 14-week-old B6FVB TRAMP-positive mice were scanned using magnetic resonance imaging. Four mice were dosed with CRC2631, and four were dosed with VNP20009; both treated four times per week. Mice were weighed and monitored daily for four weeks.

Since the CRC2631 bacteria are cleared out through the liver, the researchers also sought to establish the impact of CRC2631 on liver pathology in this bacterial cancer therapy. Two groups of 31-week-old B6FVB TRAMP-positive mice were observed, one treated with four doses of CRC2631 and the other with saline (the control group) at three-day intervals. They used histological staining in the liver to observe differences in necrosis, inflammation, and extramedullary hematopoiesis between CRC2631 and the control group. The team then tested for lethality and the maximum tolerated dose of CRC2631.

“Next, we sought to determine the in vivo tumor-targeting capability of CRC2631 in TRAMP animals.”

Using fluorescence imaging and a chloramphenicol resistance cassette, researchers were able to observe the biodistribution of CRC2631 to determine its tumor-targeting capability in TRAMP-positive mice. Since they knew that CRC2631 is filtered through the liver and that enriched colonies may be found here, researchers used the liver as a way to compare the bacterial load in tumor tissues.

The researchers also tested CRC2631’s genetic stability by gauging its likelihood of regaining toxicity and/or losing tumor targeting capability by performing longitudinal, whole genome sequencing and short nucleotide polymorphism analyses.

“To determine the genetic stability of CRC2631 inside the host, we performed longitudinal whole genome sequencing and short nucleotide polymorphism (SNP) analyses of CRC2631 prior to treatment and tumor-passaged CRC2631 in B6 TRAMP (+) mice.”

In vitro, CRC2631 directly kills prostate cancer cells, however, in vivo, it does not lead to decreased tumor burden. The researchers believe this may be due to the effects of some kind of resistance mechanism in vivo, and tested a combined treatment method of CRC2631 and Invivomab—a checkpoint blockade—in the mouse model.

“CRC2631 targets and directly kills murine and human prostate cancer cells in vitro (Supplementary Figure 2), raising the possibility that unknown resistance mechanisms protect tumor cells from CRC2631-mediated cell death in vivo.”

Results

Researchers explain that in the first two weeks of the study, mice treated with CRC2631 and VNP20009 lost a comparable amount of weight. However, in the second half of the study, VNP20009-treated animals lost progressively more weight than those treated with CRC2631. This revealed that CRC2631 is less toxic than VNP20009.

“Consistent with CRC2631 being less toxic than VNP20009, the median survival time was 142 days for VNP20009 compared to 186 days for CRC2631 (Figure 1F).”

After evaluating effects in the liver from CRC2631, they found no differences between CRC2631 and the control group in liver necrosis, inflammation, or extramedullary hematopoiesis.

“Thus, in contrast to VNP20009, CRC2631 does not cause overt liver pathology.”

They established the maximum tolerated dose to be two doses of 5 × 10^7 colony forming units, administered three days apart. In the model used in fluorescence imaging, they found that CRC2631 was significantly colonized in the tumor tissue of mice when compared to colonization in the liver and, as the dosage increased, CRC2631 quantities in tumor tissues also increased.

“Taken together, these data indicate that CRC2631^iRFP720-cat targets primary tumors and metastases.”

Researchers revealed that it would take approximately 9375 days for CRC2631 to acquire a potential mutation in any specific gene. They determined CRC2631 to be a genetically stable tumor-targeting mechanism. Next, they collected results from the CRC2631 and Invivomab immune checkpoint blockade combination.

“We turned our focus to an interaction between CRC2631 and immune cells and asked whether tumor-targeted CRC2631 generates an anti-tumor immune response that tumors rapidly inhibit via immune checkpoint mechanisms.”

They found that tumor burdens were significantly reduced in the combination treatment method, and ultimately, that CRC2631 treatment with a checkpoint blockade combination reduces the metastatic burden in mouse-modeled prostate cancer.

Conclusion

The study as a whole revealed to the researchers that CRC2631 safely targets primary tumors and metastases, is less toxic than VNP20009, does not cause overt liver pathology, and that, in combination with an immune checkpoint blockade such as Invivomab, it reduces metastatic burden in vivo in B6FVB TRAMP-positive mice.

“These findings indicate that CRC2631 is a genetically stable biologic that safely targets tumors. Moreover, tumor-targeted CRC2631 induces anti-tumor immune activity and concordantly reduces metastasis burden in the setting of checkpoint blockade.”

With more research, this method may soon be studied as an effective clinical treatment option for human prostate cancer.

Click here to read the full scientific study, published in Oncotarget.

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