Transformation Of Normal Cells Research Articles

Evaluation of the Anticancer, Antidiabetic, and In vitro Wound Healing Properties of the Aqueous and Ethanolic Extract of Hibiscus rosa-sinensis L

ABSTRACT Cancer, diabetes, and wounds are critical health challenges affecting millions of people worldwide. Cancer arises from the transformation of normal cells into tumor cells, leading to uncontrolled growth and potential spread to other parts of the body. Diabetes is a chronic metabolic disorder characterized by elevated blood sugar levels, and wounds can result from various injuries and diseases. In this study, we investigated the therapeutic potential of Hibiscus rosa-sinensis for its anticancer, antidiabetic, and in vitro wound healing activities. The anticancer activity of the ethanolic extract of H. rosa-sinensis was evaluated using the MTT (3- [4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, which showed a concentration-dependent decrease in cell proliferation and growth. The extract exhibited promising anticancer potential, which could help control cancer progression. For the antidiabetic activity, we assessed α-amylase inhibition using a colorimetric method. The extract demonstrated substantial α-amylase inhibitory activity, comparable with the standard metformin. This indicates its potential in reducing postprandial blood sugar spikes in diabetic patients. In the in vitro wound healing activity, a scratch assay was performed to measure cell migration and growth. The results showed that H. rosa-sinensis extract promoted wound closure similar to the control. The extract’s wound healing properties suggest its potential use in managing various types of wounds. Phytochemical analysis confirmed the presence of key bioactive compounds in both ethanolic and aqueous extracts of H. rosa-sinensis, supporting the observed therapeutic effects. In conclusion, H. rosa-sinensis holds promise as a potential source of novel therapeutic agent for cancer, diabetes, and wound management. The results from this study provide valuable insights into the plant’s pharmacological activities and may pave the way for the development of new herbal-based treatments for these conditions.

MiR-374a/b-5p Suppresses Cell Growth in Papillary Thyroid Carcinoma Through Blocking Exosomal ANXA1-Induced Macrophage M2 Polarization.

Papillary thyroid carcinoma (PTC), comprising 85% of all thyroid cancers, is an epithelial malignancy. The potential for malignant transformation in normal cells by thyroid cancer cells via exosomal Annexin A1 (ANXA1) delivery is investigated in this study. Our aim is to determine the impact of PTC cells on macrophage polarization through exosomal ANXA1 secretion and its implications for tumor progression.Exosomes in PTC cells were examined using transmission electron microscopy, exosome labeling, and nanoparticle tracking analysis. Real-time quantitative polymerase chain reaction was employed to quantify gene expression levels. Protein levels were determined through Western blot analysis. The interplay between genes was assessed using luciferase reporter and RNA pull-down assays. Functional experiments were conducted to investigate PTC cell proliferation and apoptosis.Our findings reveal that ANXA1 promotes PTC cell proliferation and inhibits apoptosis. Exosomes derived from PTC cells were found to promote macrophage M2 polarization. ANXA1 stimulates M2 polarization through the activation of the PI3K/AKT pathway. MicroRNA-374a-5p (miR-374a-5p) and microRNA-374b-5p (miR-374b-5p) were identified as inhibitors of ANXA1 expression and PI3K/AKT pathway activity, thereby inhibiting macrophage M2 polarization. Furthermore, miR-374a-5p and miR-374b-5p were observed to suppress PTC cell proliferation through their regulatory action on ANXA1.Our study suggests that miR-374a/b-5p inhibits PTC cell growth by blocking the macrophage M2 polarization induced by exosomal ANXA1.

Epigenetic Modulation in Cancer: Molecular Mechanisms and Therapeutic Targets – A Review

Cancer continues to be one of the leading causes of death and a major global health problem despite ongoing research efforts, advancement in medical technologies, and increased public health awareness. However, the understanding of human cancer as a heterogeneous disease has been significantly increased offering hope that the vital molecular and cellular mechanisms would pave the way for controlling cancer at its advanced stages. The transformation of normal cells into cancerous cells is a complex process achieved through a cascade of events and molecular modifications. A great deal of cancer research has been focusing on studying epigenetic alterations such as DNA methylation, histone modification, and non-coding RNA expression. These epigenetic changes modulate gene expression which is believed to play a potential role in cancer initiation, proliferation, and metastasis. This article aims to review how several aberrant epigenetic regulations impact gene expression and cellular reprogramming in cancer. It also discusses how hypomethylation can lead to increased expression of oncogenes and how hypermethylation silences key tumor suppressor genes. It also highlights how these aberrantly dysregulated genes can serve as potential therapeutic targets for cancer prevention and as biomarkers for early cancer detection.

Cellular elasticity in cancer: a review of altered biomechanical features.

A large number of studies have shown that changes in biomechanical characteristics are an important indicator of tumor transformation in normal cells. Elastic deformation is one of the more studied biomechanical features of tumor cells, which plays an important role in tumourigenesis and development. Altered cell elasticity often brings many indications. This manuscript reviews the effects of altered cellular elasticity on cell characteristics, including adhesion viscosity, migration, proliferation, and differentiation elasticity and stiffness. Also, the physical factors that may affect cell elasticity, such as temperature, cell height, cell-viscosity, and aging, are summarized. Then, the effects of cell-matrix, cytoskeleton, in vitro culture medium, and cell-substrate with different three-dimensional structures on cell elasticity during cell tumorigenesis are outlined. Importantly, we summarize the current signaling pathways that may affect cellular elasticity, as well as tests for cellular elastic deformation. Finally, we summarize current hybrid materials: polymer-polymer, protein-protein, and protein-polymer hybrids, also, nano-delivery strategies that target cellular resilience and cases that are at least in clinical phase 1 trials. Overall, the behavior of cancer cell elasticity is modulated by biological, chemical, and physical changes, which in turn have the potential to alter cellular elasticity, and this may be an encouraging prediction for the future discovery of cancer therapies.

Role of Activator Protein-1 Transcription Factor in Oral Cancer

Abstract: Cancer is a multi-step process involving alterations in epigenetic and genetic processes. Oral squamous cell carcinoma is a frequent oral malignancy that originates from the transformation of normal cells into malignant cells as a consequence of failures in a series of normal molecular and cellular processes. The mechanism of human carcinogenesis is often seen as a double-edged sword, with the body's system being thought to counteract the detrimental consequences of neoplastic cell proliferation while simultaneously promoting tumor development. Various transcription factors play a significant part in cancer regulation, with the activator protein-1 family of transcription factors (TFs) being the most prominent regulatory protein family. The Jun, Fos, ATF, and MAF protein families are all present in the AP-1 dimeric complex. While certain AP-1 proteins, including JunB and c-Fos, are known to be majorly oncogenic in function, experimental studies have shown that other AP-1 proteins, such as JunB and c-Fos, also play a critical role in tumor suppression. The aim of this review is to offer breakthrough information on the role of molecular mechanisms mediated by AP-1 TFs in tumor development and its environment.

Specificity Proteins (Sp) and Cancer.

The specificity protein (Sp) transcription factors (TFs) Sp1, Sp2, Sp3 and Sp4 exhibit structural and functional similarities in cancer cells and extensive studies of Sp1 show that it is a negative prognostic factor for patients with multiple tumor types. In this review, the role of Sp1, Sp3 and Sp4 in the development of cancer and their regulation of pro-oncogenic factors and pathways is reviewed. In addition, interactions with non-coding RNAs and the development of agents that target Sp transcription factors are also discussed. Studies on normal cell transformation into cancer cell lines show that this transformation process is accompanied by increased levels of Sp1 in most cell models, and in the transformation of muscle cells into rhabdomyosarcoma, both Sp1 and Sp3, but not Sp4, are increased. The pro-oncogenic functions of Sp1, Sp3 and Sp4 in cancer cell lines were studied in knockdown studies where silencing of each individual Sp TF decreased cancer growth, invasion and induced apoptosis. Silencing of an individual Sp TF was not compensated for by the other two and it was concluded that Sp1, Sp3 and Sp4 are examples of non-oncogene addicted genes. This conclusion was strengthened by the results of Sp TF interactions with non-coding microRNAs and long non-coding RNAs where Sp1 contributed to pro-oncogenic functions of Sp/non-coding RNAs. There are now many examples of anticancer agents and pharmaceuticals that induce downregulation/degradation of Sp1, Sp3 and Sp4, yet clinical applications of drugs specifically targeting Sp TFs are not being used. The application of agents targeting Sp TFs in combination therapies should be considered for their potential to enhance treatment efficacy and decrease toxic side effects.

Hugh John Forster Cairns. 21 November 1922—12 November 2018

John Cairns was a magnet for scientists (and non-scientists) of all types, from undergraduates to Nobel laureates. For him science was fun, and discussing science with others even more fun. Soon after finishing medical school (Oxford) at the end of the Second World War he gravitated towards research, his first publication linking the incidence of penicillin-resistant bacteria with long hospital stays. He then studied virology with Macfarlane Burnet FRS in Melbourne, Australia, after which he repaid his two years of National Service from the Second World War at the Virus Research Institute in Entebbe, Uganda. He returned to Australia (Canberra), continuing influenza virus research. However, while visiting Caltech in the 1950s, he was exposed to the emerging field of molecular biology, of which he became a pioneer. After returning to Canberra from a sabbatical with Alfred Hershey at Cold Spring Harbor in 1961, he showed that the Escherichia coli genome is circular, and demonstrated the replication fork. In 1963 he was appointed director of the Cold Spring Harbor Laboratory (CSHL). He successfully saved CSHL from bankruptcy before handing over directorship to Jim Watson (ForMemRS 1981). At CSHL he proved that the so-called Kornberg DNA polymerase was not required for replication of the E. coli genome. In the 1970s Cairns turned his attention to understanding cancer and moved to North London to direct a small research institute in Mill Hill, a satellite of the Imperial Cancer Research Fund based in central London. Cairns wrote two influential reviews on cancer plus the book Cancer: science and society , seamlessly weaving together information across disciplines, from human population levels to molecular levels, plus everything in between. He fostered multi-disciplinary basic research at the Mill Hill labs, recruiting scientists who used model organisms such as bacteria, fruit flies, slime moulds, amphibians and mice as models to explore the determinants of cell fate during development; such pathways seemed likely to be involved in the transformation of normal cells into cancer cells. Cairns created and fostered an exceptionally stimulating, interactive, nurturing and cutting-edge research environment that launched the careers of many scientists. In his own lab at Mill Hill, Cairns discovered new pathways for DNA alkylation repair in E. coli , and subsequently as professor of cancer biology at the Harvard School of Public Health he discovered what is now known as stress-induced mutagenesis, also in E. coli .

The Process and Metabolism of Chemical Carcinogenesis

The potential for DNA damage and the activation of specific oncogenic pathways that cause inflammation are present in a wide range of physical, chemical, and biological variables that are constantly present in human beings. According to certain theories, chemical carcinogens are the primary etiological factor in cancer. These substances interact either or non-covalently with the DNA, RNA, and proteins in human tissue, which helps to initiate carcinogenesis, a process in which genetic mutation and changes to the transcription of the genome take precedence. These carcinogens act as cancer cell growth initiators or promoters. When DNA, RNA, or proteins are alkylated, covalent connections are first formed with them and then the promoting action occurs. The process involves numerous molecular and cellular changes that turn normal cells into plastic cells. Although it is hypothesized that these endogenous chemical processes could cause DNA damage by inducing gene changes with the aid of reactive oxygen species. This review's focus is on the basic mechanism and metabolism of chemical carcinogenesis. Chemical carcinogens are supposedly considered to be the key etiological factor of malignancy. The covalent or non-covalent bonds between these chemical and the DNA, RNA, and proteins of human tissue help in the initiation of carcinogenesis wherein, genetic mutation and alteration in the genome transcription supervenes. These carcinogens behave as initiators or promoters of cancer cell growth. Alkylation of DNA, RNA, or proteins and the formation of covalent bonds with them begin initially followed by the promoting effect. Numerous molecular and cellular events causing the transformation of normal cells into neoplastic cells occur in the process. It is assumed though those endogenous molecular pathways could instigate mutations in respective genes with the support of reactive oxygen species, thus leading to DNA damage. Thus, this review deals with the basic mechanism and metabolism of chemical carcinogenesis.

Role of lymphatic endothelial cells as antigen presenting cells in tumor T cell immunity

During tumor development, the tumor microenvironment impacts negatively anti-tumor T cell responses. Indeed tumors develop mechanisms to avoid immunosurveillance by inducing poorly immunogenic tumors or by setting up tolerogenic mechanisms to inhibit effective immune responses. In the context of lymphangiogenic tumors, lymphatic endothelial cells (LECs) substantially expand in the tumor itself and in the tumor draining lymph node, resulting in increased lymphatic drainage, tumor cell dissemination and metastasis. Recently, LECs have been given much attention as putative unconventional antigen presenting cells. Our group and others have studied their immunoregulatory role, pointing out their contribution in adaptive immunity. Previous studies have demonstrated that LECs can directly present tumor-derived antigens to tumor-specific CD8+ T cells leading to their deletion. However, it is unknown whether LECs can directly present tumor antigens to CD4+ T cells. Using a murine tumor cell line that promotes lymphangiogenesis, we show that, when MHCII expression is abrogated in LEC, tumor growth is reduced, effector T cell functions are enhanced, whereas the phenotype of suppressive regulatory T cells seems to be impaired. These results suggest that tumor-associated LECs would function as tolerogenic antigen-presenting cells, a property that could be blocked to improve immunotherapies in cancer. Further experiments will be performed in order to confirm these results, and extend to a mouse model of non-small cell lung cancer which is initiated by transformation of normal cells and is more physiologically relevant to humans.

The Dysregulation of MicroRNAs in the Development of Cervical Pre-Cancer-An Update.

Globally in 2020, an estimated ~600,000 women were diagnosed with and 340,000 women died from cervical cancer. Compared to 2012, the number of cases increased by 7.5% and the number of deaths increased by 17%. MiRNAs are involved in multiple processes in the pathogenesis of cervical cancer. Dysregulation of miRNAs in the pre-stage of cervical cancer is the focus of this review. Here we summarize the dysregulated miRNAs in clinical samples from cervical pre-cancer patients and relate them to the early transformation process owing to human papillomavirus (HPV) infection in the cervical cells. When HPV infects the normal cervical cells, the DNA damage response is initiated with the involvement of HPV’s E1 and E2 proteins. Later, cell proliferation and cell death are affected by the E6 and E7 proteins. We find that the expressions of miRNAs in cervical pre-cancerous tissue revealed by different studies seldom agreed with each other. The discrepancy in sample types, samples’ HPV status, expression measurement, and methods for analysis contributed to the non-aligned results across studies. However, several miRNAs (miR-34a, miR-9, miR-21, miR-145, and miR-375) were found to be dysregulated across multiple studies. In addition, there are hints that the DNA damage response and cell growth response induced by HPV during the early transformation of the cervical cells are related to these miRNAs. Currently, no review articles analyse the relationship between the dysregulated miRNAs in cervical pre-cancerous tissue and their possible roles in the early processes involving HPV’s protein encoded by the early genes and DNA damage response during normal cell transformation. Our review provides insight on spotting miRNAs involved in the early pathogenic processes and pointing out their potential as biomarker targets of cervical pre-cancer.

Expression of let-7a, miR-106b and miR-29b is changed in human gastric cancer.

MicroRNA (miRNA) are small, noncoding RNA sequences that post-transcriptionally regulate the proliferation, activity and apoptosis of human gastric cancer cells by controlling various signaling cascades. Processes that involve miRNA molecules can create a specific network of interactions in a cell, and disruption of its functioning may contribute to the transformation of normal cells into cancerous cells. Aims of our survey were: 1) study the relationship between the expression of selected miRNA types (let-7a, miR-106b, miR-29b, miR-21, miR-155, miR-222) in the gastric mucosa and pathomorphological changes determined by classical histopathological methods, 2) perform in silico analysis to select target genes for selected miRNAs and to perform functional analysis of these genes. Eighty-three subjects (45 women, 38 men; mean age 39±14 years, range: 21-80 years, were examined). Among them were 18 (21.5%) patients with chronic active gastritis, 42 (50.6%) people with chronic inactive gastritis, 9 (10.8%) patients with gastric cancer and 14 (16.9%) patients without histopathological changes. The study demonstrated that mainly the expression of 3 (miR-29b, let-7a miR-106b) out of 6 selected miRNAs are significantly different depending on the site of biopsy (body of the stomach or antrum) and the group of patients. Expression of miR-106b in the antrum and body was the highest in the group of cancer patients and the lowest in patients with chronic active gastritis. The expression of let-7a differed depending on group of patients and location. The highest expression was in the body in the group with inactive gastritis and the lowest in gastric cancer. Patients with cancer had the lowest expression of miR-29b in stomach body and it was the highest in the patients with inactive gastritis in this location. Expression of miR-21 and miR-155 determinations were not statistically significant in comparison to groups or locations, and of miR-222 was not different between the groups, but only in the control group was higher in the antrum than in the body. We conclude that identification of miRNAs may represent a promising modern complementary method in the diagnosis of gastric diseases, especially cancer.

Decoding the Genetic Alteration in Genes of PARP Family and the Possible Association with HNSCC

Introduction: Genetic alterations have long been associated with the transformation of normal cells into malignant cells. Several genes are related to exhibiting the phenotype. The PARP gene family is mainly involved in maintaining genome stability. They play an important role in DNA repair and the programmed cell death process.
 Aim: To analyse the genetic alteration in PARP family and to determine its association with HNSCC.
 Materials and Methods: Cbioportal was used as the primary database for identifying the mutations and variations. The data generated in the form of oncoprint was further assessed for frequency of occurrence, type and novelty.
 Results and Discussion: It can be observed that greater amplification was found in the TIPARP gene which is 14% among all the 17 genes of the family. Also to add on, PARP 14 and PARP 15 show amplification patterns in similar groups of patients. Several types of mutations such as truncated, splicing deep deletion were found in most of the genes. The TIPARP gene was up-regulated in HNSCC patients. The Caucasians experiencing low/medium expression of TIPARP showed greater rates of survival than highly expressed African Americans. Similarly, males presenting with low or medium expression of TIPARP showed a greater rate of survival than the highly expressed females.
 Conclusion: TIPARP could be a promising prognostic marker for screening populations vulnerable to acquiring HNSCC.

Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study.

Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer. Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment. To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.

Epigenetic targeting for lung cancer treatment via CRISPR/Cas9 technology

The growth of CRISPR/Cas9 system and findings of various Cas9 protein forms along with its improved delivery methodologies has enhanced the practical applications of gene editing. Inducing desired gene of interest to correcting disease related mutations and to suppress or activate a gene of interest efficiently is now practically possible with the help CRISPR/Cas9 system. The main cause of lung cancer is the dysregulation of epigenetic markers which bring transformation in normal cells. Targeting epigenetic modification or epigenetic regulatory enzymes with the help of CRISPR/Cas9 system might be a vital step for cancer therapy.

Spectroscopic evaluation of carcinogenesis in endometrial cancer

Carcinogenesis is a multifaceted process of cancer formation. The transformation of normal cells into cancerous ones may be difficult to determine at a very early stage. Therefore, methods enabling identification of initial changes caused by cancer require novel approaches. Although physical spectroscopic methods such as FT-Raman and Fourier Transform InfraRed (FTIR) are used to detect chemical changes in cancer tissues, their potential has not been investigated with respect to carcinogenesis. The study aimed to evaluate the usefulness of FT-Raman and FTIR spectroscopy as diagnostic methods of endometrial cancer carcinogenesis. The results indicated development of endometrial cancer was accompanied with chemical changes in nucleic acid, amide I and lipids in Raman spectra. FTIR spectra showed that tissues with development of carcinogenesis were characterized by changes in carbohydrates and amides vibrations. Principal component analysis and hierarchical cluster analysis of Raman spectra demonstrated similarity of tissues with cancer cells and lesions considered precursor of cancer (complex atypical hyperplasia), however they differed from the control samples. Pearson correlation test showed correlation between cancer and complex atypical hyperplasia tissues and between non-cancerous tissue samples. The results of the study indicate that Raman spectroscopy is more effective in assessing the development of carcinogenesis in endometrial cancer than FTIR.

Targeting Protein Degradation in Cancer Treatment

The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein, we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

Genomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear. Here, we discovered that the CUL4A-DTL ligase complex targeted the DNA-PKcs protein in the NHEJ repair pathway for nuclear degradation. Overexpression of either CUL4A or DTL reduced NHEJ repair efficiency and subsequently increased the accumulation of DSBs. Moreover, we demonstrated that overexpression of either CUL4A or DTL in normal cells led to genomic instability and malignant proliferation. Consistent with the in vitro findings, in human precancerous lesions, CUL4A expression gradually increased with increasing malignant tendency and was negatively correlated with DNA-PKcs and positively correlated with γ-H2AX expression. Collectively, this study provided strong evidence that the CUL4A-DTL axis increases genomic instability and enhances the subsequent malignant transformation of normal cells by inhibiting NHEJ repair. These results also suggested that CUL4A may be a prognostic marker of precancerous lesions and a potential therapeutic target in cancer.

Cellular morphological features are predictive markers of cancer cell state

Even genetically identical cells have heterogeneous properties because of stochasticity in gene or protein expression. Single cell techniques that assay heterogeneous properties would be valuable for basic science and diseases like cancer, where accurate estimates of tumor properties is critical for accurate diagnosis and grading. Cell morphology is an emergent outcome of many cellular processes, potentially carrying information about cell properties at the single cell level. Here we study whether morphological parameters are sufficient for classification of single cells, using a set of 15 cell lines, representing three processes: (i) the transformation of normal cells using specific genetic mutations; (ii) metastasis in breast cancer and (iii) metastasis in osteosarcomas. Cellular morphology is defined as quantitative measures of the shape of the cell and the structure of the actin. We use a toolbox that calculates quantitative morphological parameters of cell images and apply it to hundreds of images of cells belonging to different cell lines. Using a combination of dimensional reduction and machine learning, we test whether these different processes have specific morphological signatures and whether single cells can be classified based on morphology alone. Using morphological parameters we could accurately classify cells as belonging to the correct class with high accuracy. Morphological signatures could distinguish between cells that were different only because of a different mutation on a parental line. Furthermore, both oncogenesis and metastasis appear to be characterized by stereotypical morphology changes. Thus, cellular morphology is a signature of cell phenotype, or state, at the single cell level.

Abstract 36: Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity

Abstract The tissue-specificity of cancer and cancer risk is a fundamental open research question. Beyond advancing our understanding of carcinogenesis, elucidating the factors underlying cancer risk may also contribute to cancer prevention. Recent studies have shown that the variation in tissue cancer risk can be explained by the number of tissue stem cell divisions occurring during the lifetime and by abnormal levels of DNA methylation. While cancer risk is likely not determined by a single factor, no other factor has been reported since to account for this fundamental variation. Here we show that cancer synthetic lethality (SL) is another strong contributor of cancer risk in human tissues. SL is a well-known type of genetic interaction where cell death occurs under the combined inactivation of two paired SL genes but not either of them alone. Targeting SLs has been recognized as a highly valuable approach for cancer treatment. We hypothesized that since down-regulated cancer SL (cSL) gene pairs reduce the viability of cancer cells, they may impede the malignant transformation of normal cells, thus modulating cancer risk. Utilizing several recently published large-scale cancer SL networks, we systematically quantified the cancer SL load (defined as the fraction of down-regulated cancer SL gene pairs) in numerous normal and cancer tissues from the TCGA and GTEx datasets. Our key findings are: 1. The cSL loads are lower in cancers vs their matched normal tissues. Furthermore, we find that the cSL load decreases progressively as cancers develop from normal tissues through multiple stages of pre-malignant lesions. These results testify that high cSL load is detrimental to cancer cells, acting as a barrier to cancer development. That is, as normal cells undergo malignant transformation, they need to reactivate at least some of the down-regulated cSL genes for the emerging cancer cells to survive. 2. In accordance with these observations, we find that cSL load in normal tissues is strongly inversely correlated with their lifetime cancer risk. 3. We find that cSL load is the first identified predictor of cancer onset time across different normal tissues - higher cSL load in the younger population is associated with later onset of cancers in that tissue. 4. cSL are important contributors of the tissue/cancer-type specificity of numerous tumor suppressor genes (like BRCA1) - that is, the activity state of cSL partners of quite a few tumor suppressor genes predicts the specific tissues in which they are known to drive cancer. Taken together, these results show that synthetic lethality load in normal tissues is a novel important biological contributor of cancer risk in humans. While synthetic lethality has been attracting tremendous attention as a way to identify cancer vulnerabilities and target them, this is the first time that its role in mediating cancer development is uncovered. Citation Format: Nishanth Ulhas Nair, Kuoyuan Cheng, Joo Sang Lee, Eytan Ruppin. Synthetic lethality across normal tissues is strongly associated with cancer risk, onset, and tumor suppressor specificity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 36.

Mutant P53 Expression Of Oral Transformed Epithelium Cell In Rats Injected By Benzo[A]Pyrene

Benzopyrene is a polycyclic aromatic hydrocarbons (PAHs) compound that can cause transformation of normal cells into malignant in order to its genotoxic,mutagenic,and carsinogenic ability. DNA mutation in tumor suppressor genes p53 make cells immortal which results in cell transformation and develops into malignancies. This study consist of five groups including the control group (without benzopyrene injection) and 4 treatment groups injected with benzopyrene each for 4 weeks (P1), 6 weeks (P2), 8 weeks (P3) and 10 weeks (P4). Therefore, the mutant p53 expression was calculated and analyzed statistically with the One Way Anova Test. There was signifficance difference in mutant p53 expression of oral transformed epithelium cell injected by benzopyrene (p=0.000) and the highest expression was at 10th week. It can be concluded that the mutant P53 expression of oral transformed epithelium cells in rats was increased after injected by benzopyrene