Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Scribd Logo
Upload

Welcome to Scribd!

  • 58 views

    Molecular Basis of Cancer 2021 - Rika

    Uploaded by

    Henry Wijaya

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd

    Molecular Basis of Cancer 2021 - Rika

    Uploaded by

    Henry Wijaya
    58 views58 pages

    Original Title

    Molecular Basis of Cancer 2021 -Rika (1)

    Copyright

    © © All Rights Reserved

    Available Formats

    PPTX, PDF, TXT or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    58 views58 pages

    Molecular Basis of Cancer 2021 - Rika

    Uploaded by

    Henry Wijaya

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 58

    Molecular Basis of Cancer:

    Genetic and Epigenetic Interactions

    Sofia Mubarika Haryana


    18 November 2021
    Kuliah S2 IKK FK KMK UGM
    Outline
    1. Cancer heterogeneity : chemoresistance and metastases
    2. Specific Cancer Biomarker - Liquid Biopsy and exo-miRNA
    3. Cancer Genetic and epigenetic – basic understanding of cancer
    4. Cancer Precision Medicine – when ?
    1. Cancer heterogeneity  chemoresistance

    What and Why heterogeneity… ?

    Health care industry. 2021


    Heterogeneity
    • Genetic heterogeneity is the result of multilineage somatic evolution of
    genetically unstable cancer cells and it is regarded as the main reason for
    failure of classic cytotoxic drugs, as well as modern targeted therapy 
    • Spatial Heterogeneity Is a Fundamental Feature of the Tumor
    Microenvironment. It is important to recognize that the orchestrated
    influence of microenvironmental components on cancer is often
    accompanied by strong regional differences (Gillies et al. 2012; Junttila and
    de Sauvage 2013).
    • Temporal heterogeneity. Heterogeneity during the course of disease
    progression (temporal heterogeneity)
    Martelooto, et al, 2016
    Cancer heterogeneity  genomic
    instability esp Tumor supressor gene,
    and repair genes  chemoresistance

    Nature .com 2015

    Heterogeneity intratumoral
     Tissue is Issue
    Reynaud et al., . Plos One, 2018
    How to detect Cancer
    heterogeneity?

    • Liquid biopsy refers to


    the sampling and
    molecular analysis of
    the biofluids of
    circulating tumor cells,
    extracellular vesicles,
    nucleic acids, and so
    forth.

    Exosome ????
    Liquid biopsy  DX and Therapy

    - ctDNA mutations
    - cfDNA Methylation
    - Exosomal mRNA/ miRNA :
    - mutations
    - Variants
    - Functions
    - Transcription analysis
    - Exosomal protein analysis

    Exosomes
    Tissue biopsy vs Liquid Biopsy
    Heterogeneity spatial and temporal

    Tissue Biopsy Liquid Biopsy

    Eslami et al, Frontiers in Oncol, 2020


    Tissue Biopsy Liquid Biopsy
    Exosome ?
    Exosomes are membrane-bound extracellular vesicles that are produced
    in the endosomal compartment of most eukaryotic cells
    Secreted into body fluid

    • Exosomes are defined as nanometre-sized vesicles, being packages of


    biomolecules ranging from 40-150 nanometres in size that are
    released by virtually every cell type in the body. ...
    • The exosomes released by regenerative cells such as stem cells, for
    example, are potent drivers of healing and repair.

    Cit : Kalluri et al, Science 2020


    Exosome :
    - the good
    - the bad
    - the ugly
    - current state

    Found in:
    • blood, serum and plasma,
    • urine,
    • cerebrospinal fluid (CSF),
    • tears,
    • milk, etc.
    • cell culture media used to
    grow various cell lines.

    Krol et al, 2021


    Biogenesis
    exosom

    Kalluri et al., Science, 2020, 367, 640


    Exosome miRNA : Carrier in Cell Communication

    Zhang et al Techno Cancer Res and Treatment 2018


    Exosomal miRNA trafficking, sorting and functioning
    Characteristics :
    • Content Very dynamics
    • According to current situation
    • 30 – 150 nm in size
    • Pass blood brain barrier
    • Stable in extreme pH,
    Temperature , Enzyme, freeze-
    thawed
    • Cell and tissue specific

    Ideal Biomarkers
    Zhang et al, Genomic, Bioinformatics, Proteomics, 2015)
    The key characteristics of exosomes – as potential for
    diagnostic and therapeutic :
    • Exosomes are nanometer sized, membrane bound vesicles released and received
    by nearly all cells in the body.
    • Exosomes play an integral role in cellular communication and regulation, of which
    we are just beginning to understand.
    • Exosome membranes contain cellular markers capable of targeting specific cell
    types.
    • Exosomes are not cells. Thus, they are non-immunogenic, more stable, and easier
    to handle from a pharmaceutical delivery view.
    • The contents of exosomes contain and deliver proteins, RNAs, DNAs and lipids
    which can be endocytosed by neighboring or distant cells, and modulate the
    recipient cells.
    Kalluri et al., Science, 2020, 367, 640
    Exosome Isolation and
    Purification Methods
    Hallmarks of Cancer -

    Hallmarks of Prostate Cancer


    Hallmarks of lung cancer
    Hallmarks of Ovary cancer
    etc
    Cancer :
    Genetics &
    Epigenetics
    Alterations
    Cancer – Genetic and Epigenetic Disease
    - miRNA dysregulated
    - lnRNA dysregulated

    CANCER

    - Oncogenes  activated oncogene


    - Tumour Suppressor Genes  inactivated

    Chen et al, Oncol Reports 2013


    Post Genome Era
    Coding RNA 1.5-2% ; Non Coding RNA 98 - 98,5 %
    Redefine Central Dogma

    CHEM 18, Why RNA, Spring 2021


    Non Coding RNA types
    Non coding
    • RNA

    Housekeeping Regulatory
    ncRNA RNA

    Short Long
    rRNA tRNA snRNA snoRNA ncRNA ncRNA
    <200nt >200nt
    Cancer - 40% preventable

    Gene Environment Interactions


    miRNA small molecules – big role • Small non coding RNA, about 17 – 24
    nt
    • Regulate gene expression through
    binding to mRNA  down regulate
    gene expression
    • Regulate physiological to
    pathological
    • From developmental to diseases
    • Found in all body fluid in exosome
    • Stable
    • Ideal biomarkers for all diseases
    include cancer
    • I miRNA can bind to hundreds of
    mRNA targets
    •
    ncRNA – Regulate Gene and Protein Expression
    Andrew
    Andrew Z.Z. Fire
    Fire
    Craig
    Craig C.
    C. Mello
    Mello

    C. elegans

    Cho WC. MicroRNAs in cancer - from research to therapy.


    Biochim Biophys Acta - Rev Cancer 2010;1805(2):209-217.
    Exosomes - Nano Molecules in body fluid
    Exosome

    Recipient cell

    Claudia Bang, Int J of Bochem and Cell Biol 2012


    miRNA in
    carcinogenesis

    Kong et al The Lancer Oncol, 2013)


    miR oncogene ( OncomiRs) and TSG ( T supressosor miRs)
    Correlation between Fragile chromosome sites and location of miRNA genes

    Copyright © 2004, The National Academy of Sciences


    Calin G. A. et.al. PNAS 2004;101:2999-3004
    miRNA in chemoresistence

    Ren & Yu, Ther N Clin Risk Manag, 2018


    miRNA and lncRNA in cancer Chemoresistence

    Wei et al, Mol. Cancer, 2019


    Genetic and epigenetic interactions

    Pannin et al, BBA Mol Gene Regul Mech. 2020


    miRNA –Target mRNA - Biomarkers
    Micro RNA - lncRNA - key role in cancer
    signalling and regulations
    • microRNA – transcribed never translated into protein
    • role in protein expression regulation by binding its mRNA targets –
    physiological and pathological, since start living until dead
    • Small molecules with big roles (1 microNA can target hundreds of mRNA)

    • Long nc RNA – 200 nt > , transcribed but never translated into protein
    • Regulator in Transcription, translation and posttranslational activities,
    • Key Regulator in Cancer Signalling
    LncRNA in cancer

    Dong et al, Frontiers in Genetics, 2018


    How can we get the answer ?
    • Tissue biopsy ? No Liquid Biopsy ? Yes
    Lnc-RNA - Wiring Signalling Circuity in Cancer

    lnRNA : key regulator in cancer signalling :


    1. LncRNA – associate wit Receptor –
    recruit kinase
    2. lncRNA mediate 2nd Messenger
    signalling molecules
    3. lncRNA modulate posttranscriptional
    activation
    4. lnRNA regulate epigenetic mofifications
    and transcriptional machinary

    Lin and Yang, Trends in Cell Biology, 2018


    a. lncRNA –
    biomarkers
    b. Liquid Biopsy:
    all body Fluid
    heterogeneity spatial
    and temporal plus

    Needed in
    Precision
    Medicine
    Cancer and Precision Medicine
    Carcinogenesis ( gene environment interaction)

    Factors involved
    1. Genetic and
    epigenetics
    2. Repair genes
    3. Ethnics and gender
    4. Heath status
    5. Lifestyle and habit

    Perera , Science, 1997


    Multistep carcinogenesis: genetic and epigenetic alterations

    Epigenetic
    dysregulation

    Carcinogenesis

    Genetic
    Mutation
    Which Environment make Cancer?
    Environmental factors

    - Preventable
    - Unpreventable

    Kaleli et al, Oncol Res & Rev 2018


    mRNA mRNA
    Tumor Supp Gen Oncogene
    Mekanisme
    regulasi
    aktivitas
    gene :
    Gene 
    Protein
    Functional genomics
    miRNA –
    regulate
    epigenetic
    regulators
    NGS / Transcriptomics :
    lncRNA and
    hallmarks of cancer
    EV lnRNA cross talk in TME

    Zhang et al, Cancer Science 2020


    miRNA in Cancer Hallmarks– diagnostic biomarker

    Zeng et al, LncRNA in Cancer Biology, 2017


    Future cancer research :
    Target terapi dg EV
    Cross
    Kingdom
    Regulations

    Wang et al, Mol Sciences, 2019


    Genetic mutation
    and epigenetic
    modification
    informing Precision
    medicine

    Koyle et al, BRI, 2017


    Cancer Precision
    Medicine need
    OMICS approaches

    Drake et a, J. Surg. Oncol, 2019


    Drake et al, Euro J. Surg Oncol, 2019

    You might also like