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Results for “Cancer Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

Acute myeloid leukemias (AML) are characterized by recurrent genomic alterations, often in transcriptional regulators, which form the basis on which current prognostication and therapeutic intervention is overlaid. In AML transformation can often be attributed to single chromosomal aberrations encoding oncogenes, such as t(15;17)-PML/RAR or t(6;9)-DEK/CAN but it is unclear how these aberrant transcription factors drive leukemic signaling and influence cellular responses to targeted therapies. Here we show that by using a novel \"subtractive interaction proteomics\" approach, the high risk AML-inducing oncogene t(6;9)-DEK/CAN directly activates signaling pathways that are driven by the ABL1, AKT/mTOR, and SRC family kinases. The interplay of these signaling pathways creates a network with nodes that are credible candidates for combinatorial therapeutic interventions. These results reveal specific interdependencies between nuclear oncogenes and cancer signaling pathways thus providing a foundation for the design of therapeutic strategies to better address the complexity of cancer signaling.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC=\"FIGDIR/small/464958_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@159295corg.highwire.dtl.DTLVardef@aa83d1org.highwire.dtl.DTLVardef@b41e11org.highwire.dtl.DTLVardef@122156e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

TGF-β Mediated Cell Adhesion Dynamics and Epithelial to Mesenchymal Transition in 3D and 2D Ovarian Cancer Models

BackgroundThree-dimensional (3D) tumor cultures in vitro have recently regained attention as they have been acclaimed to have higher similarity to in vivo tumors than cells grown in conventional monolayers (2D). Cancer cells in 2D monolayers fail to mimic the exact tumor microenvironment existing in the real clinical samples. The 3D anchorage-independent cancer models can better explain the cell adhesion properties in ovarian cancer cells.\n\nResultsTranscriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-{beta}-mediated and cell adhesion pathways. Presence of TGF-{beta} in these cell lines shows an increased invasion potential which is specific to cell type. We decided to choose two ovarian cancer cell lines as model systems to study Epithelial to Mesenchymal Transition (EMT) and cancer invasion based on their invasion potential and ability to switch the cadherins expression. TGF-{beta} modulation in EMT and cancer invasion was successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluations in 3D and 2D models demonstrate that the addition of the exogenous TGF-{beta} can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-{beta} receptor kinase I inhibitor (LY364947) can revert TGF-{beta} effect in these cells.\n\nConclusionsIn a nutshell, TGF-{beta} can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis.

cancer biology↗

bioRxiv2018

The landscape of viral associations in human cancers

Potential viral pathogens were systematically investigated in the whole-genome and transcriptome sequencing of 2,656 donors as part of the Pan-Cancer Analysis of Whole Genomes using a consensus approach integrating three independent pathogen detection pipelines. Viruses were detected in 382 genomic and 68 transcriptome data sets. We extensively searched and characterized numerous features of virus-positive cancers integrating various PCAWG datasets. We show the high prevalence of known tumor associated viruses such as EBV, HBV and several HPV types. Our systematic analysis revealed that HPV presence was significantly exclusive with well-known driver mutations in head/neck cancer. A strong association was observed between HPV infection and the APOBEC mutational signatures, suggesting the role of impaired mechanism of antiviral cellular defense as a driving force in the development of cervical, bladder and head neck carcinoma. Viral integration into the host genome was observed for HBV, HPV16, HPV18 and AAV2 and associated with a local increase in copy number variations. The recurrent viral integrations at the TERT promoter were coupled to high telomerase expression uncovering a further mechanism to activate this tumor driving process. High levels of endogenous retrovirus ERV1 expression is linked to worse survival outcome in kidney cancer.

cancer biology↗

bioRxiv2018

Systems-level properties of EGFR/Ras/ERK signalling amplify local signals to generate gene expressionplasticity

The EGFR/Ras/ERK signalling pathway is a driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. Using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522, we found that ERK activity in invasive cells is similar in amplitude to isogenic non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. Our analysis reveals that this diversification arises from systems-level functions of the pathway, including intracellular amplification of amphiregulin-mediated paracrine signalling and differential kinetic filtering by genes including Fra-1, c-Myc, and Egr1. Our findings establish a mechanism for the generation of non-genetic tumour cell plasticity arising from the specific quantitative properties of a signal transduction pathway.

cancer biology↗

bioRxiv2018

TGF-b2, catalase activity, H2O2 output and metastatic potential of diverse types of tumour

Theileria annulata is a protozoan parasite that infects and transforms bovine macrophages causing a myeloid-leukaemia-like disease called tropical theileriosis. TGF-{beta}2 is highly expressed in many cancer cells and is significantly increased in Theileria-transformed macrophages, as are levels of Reactive Oxygen Species (ROS), notably H2O2. Here, we describe the interplay between TGF-{beta}2 and ROS in cellular transformation. We show that TGF-{beta}2 drives expression of catalase to reduce the amount of H2O2 produced by T. annulata-transformed bovine macrophages, as well as by human lung (A549) and colon cancer (HT-29) cell lines. Theileria-transformed macrophages attenuated for dissemination express less catalase and produce more H2O2, but regain both virulent migratory and matrigel traversal phenotypes when stimulated with TGF-{beta}2, or catalase that reduce H2O2 output. Increased H2O2 output therefore, underpins the aggressive dissemination phenotype of diverse tumour cell types, but in contrast, too much H2O2 can dampen dissemination.

cancer biology↗

bioRxiv2018

Single-cell RNA sequencing reveals a dynamic stromal niche within the evolving tumour microenvironment

Non-cancerous stromal cells represent a highly diverse compartment of the tumour, yet their role across tumour evolution remains unclear. We employed single-cell RNA sequencing to determine stromal adaptations in murine melanoma at different points of tumour development. Naive lymphocytes recruited from lymph nodes underwent activation and clonal expansion within the tumour, prior to PD1 and Lag3 expression, while tumour-associated myeloid cells promoted the formation of a suppressive niche through cytokine secretion and inhibitory T cell interactions. We identified three temporally distinct cancer-associated fibroblast (CAF) populations displaying unique signatures, and verified these in human datasets. In early tumours, immune CXCL12/CSF1 and complement-expressing CAFs supported recruitment of macrophages, whereas contractile CAFs became more prevalent in later tumours. This study highlights the complex interplay and increasing diversity among cells that co-evolve with the tumour, indicating that from early stages of development, stromal cells acquire the capacity to modulate the immune landscape towards suppression.

cancer biology↗

bioRxiv2018

Computational metabolism modeling predicts risk of distant relapse-free survival in breast cancer patients

AimsDifferences in metabolism among breast cancer subtypes suggest that metabolism plays an important role in this disease. Flux Balance Analysis is used to explore these differences as well as drug response.\n\nMaterials & MethodsProteomics data from breast tumors were obtained by mass-spectrometry. Flux Balance Analysis was performed to study metabolic networks. Flux activities from metabolic pathways were calculated and used to build prognostic models.\n\nResultsFlux activities of vitamin A, tetrahydrobiopterin and beta-alanine metabolism pathways split our population into low- and high-risk patients. Additionally, flux activities of glycolysis and glutamate metabolism split triple negative tumors into low- and high-risk groups.\n\nConclusionsFlux activities summarize Flux Balance Analysis data and can be associated with prognosis in cancer.

cancer biology↗

bioRxiv2018

Ribosomal stress-induced senescence as a novel pro-senescence strategy for p16 positive basal-like breast cancer

Re-engaging the senescent programme represents an attractive yet underexplored strategy for cancer therapy, particularly for those tumour subtypes where targeted agents are limited or unavailable. Here, we identify a specific subset of ribosomal proteins as novel pro-senescence therapeutic targets for a highly aggressive subtype of breast cancer, p16 positive basal-like breast cancer. Mechanistically, ribosomal stress-induced senescence generates a stable cell cycle arrest, is dependent on endogenous p16 triggering a resensitisation to the p16/RB tumour suppressor axis, followed by establishment of a senescence-associated secretory phenotype, and is independent of DNA damage. Conversely, ribosomal protein knockdown in a p16 negative breast cancer model results in caspase-mediated apoptosis. Importantly, individual ribosomal protein loss is well tolerated by a panel of normal human cells. We demonstrate a reciprocal feedback loop between loss of RPS3A and RPS7 at both the transcriptional and post-transcriptional level during ribosomal stress-induced senescence. Further, our ribosomal hits are co-ordinately dysregulated in breast cancer, with elevated expression associated with a poor prognosis. Clinical relevance is demonstrated in tissue microarrays, and a RPS3AHIGHRPS7HIGH signature is associated with an earlier disease onset and synergises with p16 to further worsen patient outcome. We conclude that dysregulation of ribosomal proteins constitutes a cancer cell-specific mechanism of senescence evasion and that engaging ribosomal stress-induced senescence may be relevant for future pro-senescence therapies.

cancer biology↗

bioRxiv2018

A mathematical framework for modelling the metastatic spread of cancer

Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network (tumour-induced angiogenesis), they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer.\n\nTo shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner -- a multi-grid, hybrid, individual-based approach. This framework accounts for the spatio-temporal evolution of mesenchymal- and epithelial-like cancer cells, as well as MT1-MMP and MMP-2 dynamics, and interactions with the extracellular matrix.\n\nUsing computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs like MMP-2.

cancer biology↗

bioRxiv2018

Proliferation Saturation Index in an adaptive Bayesian approach to predict patient-specific radiotherapy responses

PurposeRadiotherapy prescription dose and dose fractionation protocols vary little between individual patients having the same tumor grade and stage. To personalize radiotherapy a predictive model is needed to simulate radiation response. Previous modeling attempts with multiple variables and parameters have been shown to yield excellent data fits at the cost of nonidentifiability and clinically unrealistic results.\n\nMaterials and MethodsWe develop a mathematical model based on a proliferation saturation index (PSI) that is a measurement of pre-treatment tumor volume-to-carrying capacity ratio that modulates intrinsic tumor growth and radiation response rates. In an adaptive Bayesian approach, we utilize an increasing number of data points for individual patients for predicting response to subsequent radiation doses.\n\nResultsModel analysis shows that using PSI as the only patient-specific parameter, model simulations can fit longitudinal clinical data with high accuracy (R2=0.84). By analyzing tumor response to radiation using daily CT scans early in the treatment, response to the remaining treatment fractions can be predicted after two weeks with high accuracy (c-index=0.89).\n\nConclusionThe PSI model may be suited to forecast treatment response for individual patients and offer actionable decision points for mid-treatment protocol adaptation. The presented work provides an actionable image-derived biomarker prior to and during therapy to personalize and adapt radiotherapy.

cancer biology↗

bioRxiv2018

Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers

Treatment resistance, relapse and metastasis remain critical issues in some challenging cancers, such as chondrosarcomas. Boron-neutron Capture Therapy (BNCT) is a targeted radiation therapy modality that relies on the ability of boron atoms to capture low energy neutrons, yielding high linear energy transfer alpha particles. We have developed an innovative boron-delivery system for BNCT, composed of multifunctional fluorescent mesoporous silica nanoparticles (B-MSNs), grafted with an activatable cell penetrating peptide (ACPP) for improved penetration in tumors and with Gadolinium for magnetic resonance imaging (MRI) in vivo. Chondrosarcoma cells were exposed in vitro to an epithermal neutron beam after B-MSNs administration. BNCT beam exposure successfully induced DNA damage and cell death, including in radio-resistant ALDH+ cancer stem cells (CSCs), suggesting that BNCT using this system might be a suitable treatment modality for chondrosarcoma or other hard-to-treat cancers.

cancer biology↗

bioRxiv2018

Radtools: R utilities for smooth navigation of medical image data

The radiology community has adopted several widely used standards for medical image files, including the popular DICOM (Digital Imaging and Communication in Medicine) and NIfTI (Neuroimaging Informatics Technology Initiative) standards. These file formats include image intensities as well as potentially extensive metadata. The NIfTI standard specifies a particular set of header fields describing the image and minimal information about the scan. DICOM headers can include any of over 4,000 available metadata attributes spanning a variety of topics. NIfTI files contain all slices for an image series, while DICOM files capture single slices and image series are typically organized into a directory. Each DICOM file contains metadata for the image series as well as the individual image slice.\n\nThe programming environment R is popular for data analysis due to its free and open code, active ecosystem of tools and users, and excellent system of contributed packages. Currently, many published radiological image analyses are performed with proprietary software or custom unpublished scripts. However, R is increasing in popularity in this area due to several packages for processing and analysis of image files. While these R packages handle image import and processing, no existing package makes image metadata conveniently accessible. Extracting image metadata, combining across slices, and converting to useful formats can be prohibitively cumbersome, especially for DICOM files.\n\nWe present radtools, an R package for smooth navigation of medical image data. Radtools makes the problem of extracting image metadata trivially simple, providing simple functions to explore and return information in familiar R data structures. Radtools also facilitates extraction of image data and viewing of image slices. The package is freely available under the MIT license at https://github.com/pamelarussell/radtools and is easily installable from the Comprehensive R Archive Network (https://cran.r-project.org/package=radtools).

cancer biology↗

bioRxiv2018

Single Agent and Synergistic Activity of Maritoclax with ABT-263 in Nasopharyngeal Carcinoma (NPC) Cell Lines

ObjectiveThe BCL-2 anti-apoptotic proteins are over-expressed in many cancers and hence are attractive therapeutic targets. In this study we tested the sensitivity of two NPC cell lines HK1 and C6661-1 to Maritoclax which is reported to repress anti-apoptotic protein MCL-1 and BH3 mimetic ABT-263 which selectively inhibits anti-apoptotic proteins BCL-2, BCL-XL and BCL-w. We investigated the sensitization of the NPC cell lines to these drugs using the SYBR Green I assay and 3D NPC spheroids.\n\nResultsWe report that Maritoclax repressed MCL-1, BCL-2, and BCL-XL in a dose- and time-dependent manner and displayed a single agent activity in inhibiting cell proliferation of the NPC cell lines. Moreover, combination of Maritoclax and ABT-263 exhibited synergistic cell proliferation effect in the HK1 cell line. Similar results were obtained in the 3D spheroids. More notably, 3D spheroids either treated with single agent Maritoclax or combination with ABT-263 over 10 days did not develop resistance to the treatment rapidly. Collectively, the findings illustrate that Maritoclax as a single agent or combination with BH3 mimetics could be a potential treatment strategy for NPC but further studies in preclinical models are warranted to fully unravel the prospects of these drugs.

cancer biology↗

bioRxiv2018

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

Tumor immune microenvironment (TIME) plays an important role in metastasis and immunotherapy. However, it has been not much known how to classify TIMEs and how TIMEs are genetically regulated. Here we showed that tumors were classified into TIME-rich, -intermediate and -poor subtypes which had significant differences in clinical outcomes, abundances of tumor-infiltrating lymphocytes (TILs), the degree of key immune programs activation, and immunotherapy response across 13 common cancer types (n= [~]6,000). Furthermore, TIME-intermediate/-poor patients had significantly more inherited genetic defects (i.e., functional germline variants) in natural killer (NK) cells, antigen processing and presentation (APP) and Wnt signaling pathways than TIME-rich patients, and so did cancer patients than non-cancer individuals (n=4,500). These results suggested that individuals who had more inherited defects in NK cells, APP and Wnt pathways had a higher risk of developing cancers. Moreover, in the 13 common cancers the number of inheritably defected genes of NK cells was significantly negative-correlated with patients survival, TILs abundance in TIMEs and immunotherapy response, suggesting that inherited defects in NK cells alone were sufficient to shape TILs recruitment, clinical outcome, and immunotherapy response, highlighting that NK cell activation was required in the 13 cancer types to drive the recruitment of immune troops into TIMEs. Thus, we proposed that cancer was a disease of NK cell inherited deficiencies. These results had implications in identifying of high-risk individuals based on germline genomes, implementing precision cancer prevention by adoptive transfer of healthy NK cells, and improving existing immunotherapies by combining of adoptive NK cell transfer (i.e., converting TIME-intermediate/-poor tumors into TIME-rich tumors) and anti-PD-1 or CAR-T therapy.\n\nContactEW (edwin.wang@ucalgary.ca)

cancer biology↗

bioRxiv2018

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity

The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.

cancer biology↗

bioRxiv2018

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of HGSC patients relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here we found that in comparison to normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. To further differentiate the necessity of TCA cycle enzymes in ovarian cancer progression, we found that only wildtype isocitrate dehydrogenase I (IDH1) is both significantly increased in HGSC cells in spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in primary HGSC patient tumors. Pharmacological inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at proliferation promoting gene loci (PCNA and MCM3), which led to decreased mRNA expression. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wildtype IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence. Therefore, inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a pro-senescent therapy.

cancer biology↗

bioRxiv2018

A Novel Melatonergic Signature Predicts Reccurence Risk and Therapeutic Response in Breast Cancer Patients

ASMT is a key determinant of the levels of released melatonin. Though melatonin has been shown to exhibit anti-cancer activity and prevents endocrine resistance in breast cancer, the role of ASMT in breast cancer progression remains unclear. In this retrospective study, we analyzed gene expression profiles from thousands of patients and found that ASMT expression was significantly lower in breast cancer tumors relative to healthy tissue. Among cancer patients, those with greater expression had better relapse-free survival outcomes and longer metastasis-free survival times, and they also experienced longer periods before relapse or distance recurrence following tamoxifen treatment. Administration of melatonin, in combination with tamoxifen, further promoted cancer cell death by promoting apoptosis. Motivated by these results, we devised an ASMT gene signature that identifies low-risk cases with great accuracy. This signature was validated using both mRNA array and RNAseq datasets. Intriguingly, patients who are classified as high-risk benefit from adjuvant chemotherapy, and those with grade II tumors who are classified as low-risk exhibit improved overall survival and distance relapse-free outcomes following endocrine therapy. Our findings more clearly elucidate the roles of ASMT, provide strategies for improving the efficacy of tamoxifen treatment, and help to identify those patients who may maximally benefit from adjuvant or endocrine therapies.

cancer biology↗

bioRxiv2018

NDRG2 Regulates Adherens Junction Integrity to Restrict Colitis and Tumorigenesis

Paracellular barriers play an important role in the pathogenesis of IBDs and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumor suppressor gene and inhibits colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear. Here, We found that intestine-specific Ndrg2 deficiency caused mild spontaneous colitis with ageing, aggravated DSS and TNBS induced colitis, increased AOM-DSS induced colitis-associated tumor. Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhancing the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination, and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation. These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays important role in gut homeostasis maintenance and colitis-associated tumor development. SUMMARYAdherens junctoin (AJ) as the key part of intestinal epithelial barrier plays important role in the pathogenesis of IBDs. Intestinal specific Ndrg2 loss attenuates E-cadherin expression and disrupts the integrity of AJ structure which is feasible for colitis and tumor development.

cancer biology↗