Thought provoking talk from John Dick at #ISSCR2016 on cancer stem cells

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Dr. John Dick gave a great talk yesterday on cancer stem cells here at ISSCR 2016. Below I summarize his talk and as always with these meeting blogs, the post is not polished and is more of a stream of the speaker’s main points. He started out broadly with a nice introduction to this area of research.

There’s a lot of controversy around cancer stem cells (CSC). How many tumors have CSCs? How different are cells within the same tumor?

The normal hierarchical organization of hematopoiesis is disrupted in AML. Are CSC properties clinically relevant in leukemia?

Here the focus is on leukemic stem cells (LSC).  If a patient’s cells can engraft a mouse then that patient has much worse survival. This engraftment predicts relapse. They have developed a LSC prognostic score. NMP1mut FLT3-ITD neg cells are mentioned. miRNA signatures and epigenetics matter for survival. Big picture conclusion: stem cell properties are very important to the disease.

More genetic studies. Branching tumor evolution during leukemia development: what is the role of stem cells? They did deep targeted sequencing of the genes known to be important for AML. They discovered a common ancestor gene commonly mutated in AML. (Shlush, Nature 2014). DNMT3a mutation was present in the common ancestor cell. Leukemia blasts can have the DNMT3a and NPM1C alleles, but many only have one marker (suggesting clonal evolution).

This raises many interesting questions.

Where does relapse come from? What is cellular origin? Did the chemo induce changes? Or are there residual cells that then spur a tumor comeback?

There’s no definitive marker for LSC.

Evidence of a long evolution in the preleukemic phase. One model is that relapse originates from rare LSC that evolve before diagnosis and survive therapy.

A fascinating point–cells that preferentially grow in the mouse xenograft are not the predominant one in the patient at presentation but rather the ones that will later kill the patient through relapse. Another model is that relapse stems from a rare CD33+ subset.

1 thought on “Thought provoking talk from John Dick at #ISSCR2016 on cancer stem cells”

  1. Paul have you every seen …….what are CSC Cancer stem cells ?

    “5-8-2015 White paper : Cancer Stem Cells Cell Surface Markers

    To: Annie Brandt CEO of Best answer for Cancer Foundation

    Three key terms antigen presentation (be it protein or cell–cell interaction) potency (blastomere pluripotent stem cells are the gold standard) and migration (or in cancer know as metastasis) and a possible answer to your question of Cancer Stem cell and what are they? You are more that welcome to share this…

    Highly tumorigenic subpopulation of cancer cells expressing or lacking the cell surface markers CD10, CD24, CD44, CD133. Stro-1 and epithelial-specific antigen (ESA) CAMs. You can substitute any CAM for any organ to be more comprehensive or inclusive tumor specific ….

    Why is CD24 key to mesenchymal stem cells …..why are they very high in blastomere pluripotent stem cells 24% vs. adult MSC 0-1 % ….Lanza MSC papers on

    1. What is CD 24 “Signal transducer CD24 also known as cluster of differentiation 24 or heat stable antigen CD24 (HSA) is a protein that in humans is encoded by the CD24gene.[1] CD24 is a cell adhesion molecule.” Very important and “CD24 is a glycoprotein expressed at the surface of most B lymphocytes and differentiating neuroblasts. This gene encodes a sialoglycoprotein that is expressed on mature granulocytes and in many B cells. “ And we now know on early MSC from blastomere pluripotent stem cells –Lanza MSC papers

    2. What is CD44 homing receptor know a lot about this ….. “CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on Chromosome 11.[1] CD44 has been referred to as HCAM (homing cell adhesion molecule), Pgp-1 (phagocyticglycoprotein-1), Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.” what is metastases you got it ….migration

    3. CD10 this is the blast state of the immature cells “Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP),cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.[1] It also degrades the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer’s disease.” And we now know on early MSC from blastomere pluripotent stem cells –Lanza MSC papers

    4. Stro-1 What is Stro-1? ” Stro-1 is the best-known mesenchymal stem cell marker. However, despite its bone marrow origin, its localization in bone marrow has never been demonstrated. By immunofluorescence staining, it is shown that ∼ 0.74% of nucleated bone marrow cells expressed Stro-1. Also found that ∼ 8.7% of CD34-expressing cells expressed Stro-1, and more than 20% of Stro-1-expressing cells did not express CD34. In adipose tissue Stro-1 expression was identified in the endothelium of arterioles and capillaries. Stro-1 was also localized in the endothelium of some but not all adipose tissue veins. Endothelial expression of Stro-1 was also identified in blood vessels in penis and in leg muscles, but not in other tested tissues. In these other tissues, Stro-1 was scantly expressed near but not in blood vessels. These variable and endothelial expression patterns of Stro-1 point to a need to re-examine published data that relied on Stro-1 as a mesenchymal stem cell marker.”

    Lanza found that Stro-1 was negative for his hMSC blastomere pluripotent stem cells vs. very positive for adult MSC ….so if you have Stro-1 in high expression your potency will be varied and low…An err of many MSC researchers because of the maturity of MSC from EMT…..

    5. “ESA Or CD326 Ep-CAM consists of two glycoproteins, 34 and 39 kDa, sometimes designated epithelial antigen, epithelial specific antigen, and epithelial glycoprotein. In paraffin sections, the protein is detected with mAbs like Ber-EP4 and MOC-31. The glycoproteins are located on the cell membrane surface and in the cytoplasm of virtually all epithelial cells with the exception of most squamous epithelia, hepatocytes, renal proximal tubular cells, gastric parietal cells and myoepithelial cells.”

    6. CD133 “CD133 antigen also known as prominin-1 is a glycoprotein that in humans is encoded by the PROM1gene.[1][2] It is a member of pentaspan transmembrane glycoproteins (5-transmembrane, 5-TM), which specifically localize to cellular protrusions. While the precise function of CD133 remains unknown, it has been proposed to act as an organizer of cell membrane topology” “Tissue distribution[edit]

    CD133 is expressed in hematopoietic stem cells,[4] endothelial progenitor cells,[5] glioblastoma, neuronal andglial stem cells,[6] various pediatric brain tumors,[7] as well as adult kidney, mammary glands, trachea, salivary glands, placenta, digestive tract, testes, and some other cell types.[8][9]”

    7. All these CAM reagents are important because of EMT

    “Epithelial to Mesenchymal Transition (EMT) describes a mechanism by which cells lose their epithelial characteristics and acquire more migratory mesenchymal properties. This transient and reversible process is classified into three subtypes that are dependent on the biological and functional setting in which it occurs. This illustration represents general pathways in the scientific literature and is not to be considered comprehensive nor definitive.

    Type 1 EMT during development is essential for gastrulation, neural crest cell migration, and organ development. EMT generates fibroblasts following tissue injury that assist in local wound healing.

    Type 2 Persistent EMT following attenuation of inflammation can result in organ fibrosis.

    Type 3 EMT results in the transformation of epithelial cells into the invasive metastatic mesenchymal cells that underlie cancer progression.”

    “Loss of Tight Junctions, Adherens Junctions, and Desmosomes > Disassembly of specialized cell-cell contacts leads to redistribution of cytoskeletal proteins and disruption of the apical-basal cell polarity of epithelial cells. > Key Molecules: Actin, α-Actinin, α-Catenin, β-Catenin, Claudins, E-Cadherin, Desmogleins, Desmocollin, JAM, Occludin, Plakoglobin, Plakophilin, Vinculin, Zona Occludens

    Cytoskeletal Changes Formation of actin stress fibers that anchor to focal adhesion complexes to begin to promote cell migration. > Key Molecules: Actin, Cytokeratins, S100A4, α-Smooth Muscle Actin, Vimentin

    Transcriptional Shift Suppression of epithelial genes and activation of mesenchymal genes is mediated by Snail, ZEB, and bHLH family transcription factors. Vimentin is upregulated and extracellular deposition of Fibronectin is increased. > Key Molecules: FoxC2, Goosecoid, LEF-1, Snail 1, Snail 2 (Slug), Twist-1, ZEB1, ZEB2

    Increased Migration and Motility > Upregulation of N-Cadherin, secretion of matrix metalloproteases, and stimulation of integrins by extracellular matrix proteins facilitates cell motility. > Key Molecules: N-Cadherin, FAK, Fibronectin, α5β6 Integrin, Laminin-5, SPARC, Syndecan-1, Vitronectin these are your cancer causing molecules”

    Embryonic DC cells ..Why? …..homogeneous population easy of manufacturing and they are the most potent …..Do they migrate like hMSC mesenchymal cells? ….unknown

    Take in concretion the dendritic cells What are DC ? “Dendritic cells (DCs) are antigen-presenting cells (also known as accessory cells) of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system.”
    And “The innate immune system is an evolutionarily older defense strategy, and is the dominant immune system found in plants,fungi, insects, and primitive multicellular organisms.[3]
    The major functions of the vertebrate innate immune system include:
    • Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines
    • Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells”
    • The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialised white blood cells
    • Activation of the adaptive immune system through a process known as antigen presentation”
    Acting as a physical and chemical barrier to infectious agents. “Dendritic cells (DC) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), and the inner mucosal lining of the nose, lungs, stomach, and intestines.[2] They are named for their resemblance to neuronal dendrites, but dendritic cells are not connected to the nervous system. Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive immune systems.”
    Bottom line conclusion: Lanza abstract below from reference # 2 say it best for possibly the gold standard cells to Cure most auto immunity and most cancers with dendritic antigen presentation cells , IMO


    1. Identification of Pancreatic Cancer Stem Cells Chenwei Li,1 David G. Heidt,1 Piero Dalerba,4 Charles F. Burant,2,3 Lanjing Zhang,3 Volkan Adsay,4 Max Wicha,3 Michael F. Clarke,5 and Diane M. Simeone1,2 Cancer Res 2007; 67: (3). February 1, 2007

    2. Link to Lanza ‘s papers…Mesenchymal Stem Cell Population Derived from Human Pluripotent Stem Cells Displays Potent Immunomodulatory and Therapeutic Properties Erin
    March 20, 2014 | See the paper »

    3. Human ESC-Derived MSCs Outperform Bone Marrow MSCs in the Treatment of an EAE Model of Multiple Sclerosis
    July 8, 2014 | See the paper »

    4. Stem Cells Dev. 2011 Oct;20(10):1747-52. doi: 10.1089/scd.2010.0564. Epub 2011 Feb 24.
    Tissue distribution of mesenchymal stem cell marker Stro-1.
    Lin G1, Liu G, Banie L, Wang G, Ning H, Lue TF, Lin CS.

    5. Products for EMT Research Species are at R and D Systems

    6. Wikipedia

    Lanza abstract from reference #2
    “ Mesenchymal stem cells (MSCs) are being tested in a wide range of human diseases; however, loss of potency and inconsistent quality severely limit their use. To overcome these issues, we have utilized a developmental precursor called the hemangioblast as an intermediate cell type in the derivation of a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs). This method circumvents the need for labor-intensive hand-picking, scraping, and sorting that other hESC-MSC derivation methods require. Moreover, unlike previous reports on hESC-MSCs, we have systematically evaluated their immunomodulatory properties and in vivo potency. As expected, they dynamically secrete a range of bioactive factors, display enzymatic activity, and suppress T-cell proliferation that is induced by either allogeneic cells or mitogenic stimuli. However, they also display unique immunophenotypic properties, as well as a smaller size and > 30,000-fold proliferative capacity than bone marrow-derived MSCs. In addition, this is the first report which demonstrates that hESC-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2). This is also the first report which shows that hESC-MSCs have therapeutic efficacy in two different autoimmune disorder models, including a marked increase in survival of lupus-prone mice and a reduction of symptoms in an autoimmune model of uveitis. “Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.”

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