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Premium member Presentation Transcript STEM CELLS IN SOLID TUMORS CANCER STEM CELL (CSC) : STEM CELLS IN SOLID TUMORS CANCER STEM CELL (CSC) What are stem cells? : ** Stem cells are unspecialized immature cells that can renew themselves through cell division for long periods of time. ** They are necessary for our survival. Skin stem cells renew and repair our skin. Cells in our bone marrow generate the different cell types in our blood. ** Under specific conditions, physiological or experimental, stem cells can differentiate along distinct lineages through systemic differentiation steps generating progenitors to the final stage of differentiation: Muscle cells, nerve cells, bone cells… etc ** The blood system has the best described normal stem cells. What are stem cells?Types of stem cells: Embryonic stem cells (pluripotent): ** They have the potential to generate all cell types in any organ or tissue in the body ** They come from a blastocyst, a small sphere of cells that results from cell division in a fertilized ovum. ** For research purposes, cells are harvested from the inner cell mass of the blastocyst when it is approximately six days old and consists of around 200 cells Types of stem cellsTypes of stem cells: Adult stem cells (multipotent stem cells): They are postembryonic stem cells required for normal cellular turnover and repair The best example is the hematopoietic stem cell but they are found in nearly every major organ They are relatively undifferentiated cells that are able to maintain their own numbers for life through continuous division Their progeny can differentiate into various cell lineages They divide slowly and this reduces the rate at which stem cells acquire DNA mutations Types of stem cells How can stem cells be used to treat diseases? : Stem cells as “REPLACEMENT PARTS”: A wide range of diseases (heart disease, Parkinson’s, Alzheimer’s, diabetes, motor neuron disease, etc.) may be amenable to stem cell therapy. Stem cells were directed to the appropriate place in the body and become the appropriate cell type. Ex. stem cells could be made to migrate to an injured spinal cord and become nerve cells to cure paralysis How can stem cells be used to treat diseases? How can stem cells be used to treat diseases? : 2) Developing drug therapies: It is possible to make stem cells that are genetically identical to those of a patient with a disease. The stem cells can be made to generate the cell type that is defective in that disease. By studying these cells, we can gain insight into what goes wrong at the molecular level in the disease. We can also use these cells to test drugs that might block the progression of the disease How can stem cells be used to treat diseases?Cancer stem cell theory: The idea of cancer cells arising from a common origin has been thoroughly explained and published as the Unitarian or Trophoblastic theory of cancer in 1950. It states that cancer--differentiated trophoblast proliferation-- is part of the healing process, and the disease only manifests if its control ( immune response and nutrition ) are impeded. Cancer stem cell theoryCancer stem cell theory: There are two competing visions of tumors. Old cancer model: 1) All tumor cells can form new tumors and are therefore equally tumorigenic. 2) Unregulated growth is due to serial acquisition of genetic events leading to the expression of genes that promote cell proliferation with concomitant silencing of growth inhibitory genes and blunting of cell death. 3) Cancer is a proliferative disease. Cancer stem cell theoryCancer stem cell theory: New cancer model: 1) Tumors arise from cells termed cancer stem cells that have properties of normal stem cells, particularly self-renewal and multipotentiality (a minority) of tumor cells. 2) Unregulated cell growth is due to a disruption in the regulatory mechanism in stem cell renewal . 3) Cancer is a stem cell disorder and not a simple mechanism whereby cell proliferation is disrupted. Cancer stem cell theoryCancer stem cell theory: These CSCs cells persist in tumors as a distinct population that likely causes relapses and metastasis. This theory explains why are many cancers so difficult to treat. Cancer stem cell theoryCancer stem cell theory: Why stem cells? Only stem cells have the ability to self renew and neoplasia is essentially dysregulated self renewal Stem cells are long-lived cells which can acquire the necessary number of sequential mutations to convert a normal cell into a malignant one. Cancer stem cell theoryAre we targeting the right cells?: Conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate a new one. A population of CSCs, which gave rise to it, remains untouched and may cause a relapse of the disease. Development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease , where little progress has been made in recent years. Are we targeting the right cells?WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor cells (blue) but may spare stem cells (yellow) that can give rise to a new tumor. In theory, killing cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance. : WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor cells (blue) but may spare stem cells (yellow) that can give rise to a new tumor. In theory, killing cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance. What are Cancer Stem Cells? : Cells that have properties of normal stem cells: 1) The abilities to self-renew . 2) Tha ability to differentiate into multiple cell types. 3) They form a distinct population in tumors that likely causes disease relapse and metastasis . What are Cancer Stem Cells?Self-renewal of stem cells: Self-renewal of stem cells The concept of self-renewal is crucial to understand CSC, and also to get insight on the mechanism by which current therapies might evade the available treatments.Self-renewal of stem cells: Provides the cell with the ability to undergo infinite cellular divisions with only few of the stem cells dividing at a particular time. 2) The doubling time of most stem cells is relatively long , as compared to their immediate progenitors, which replicate with shorter doubling times (Repair of DNA damage). 3) In some stem cells at division the `mother’ cell retain the original chromosome while providing the daughter with the newly formed chromosome (Chromosomal preservation) → minimizes mutation in the mother cell. Self-renewal of stem cellsCSC Development: The molecular pathways for stem cell differentiation are complex indicating that dysregulation could occur at multiple sites to turn off the homeostatic balance and create abnormal cells, or cancer cells, also referred as malignant cells or transformed cells. CSC DevelopmentNormal Stem Cells vs. Cancer Stem Cells: The stem cells in tumors (CSCs) are not the same type of stem cells being explored as potential therapies to treat degenerative diseases. But they develop because of mutations that accumulate over years and often decades. The mutations are thought to promote the tumor stem cells' ability to proliferate, eventually leading to cancer Normal Stem Cells vs. Cancer Stem CellsEvidence for the presence of CSC : 1) In exp. Animal research, efficient tumor formation to establish a tumor. This was formerly explained by: ** Poor methodology (loos of cell viability during transfer). ** The critical importance of the microenvironment. ** The particular biochemical surroundings of the injected cells. According to CSC theory only a small fraction of the injected cells, the CSC , have the potential to generate a tumor. In human AML the frequency of these cells is less than 1 in 10,000. Evidence for the presence of CSCEvidence for cancer stem cells : 2) Tumor heterogeneity: Most umors are very heterogeneous and heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types ( have a multidifferentiative potential ), a classical hallmark of stem cells. Evidence for cancer stem cellsCSC- PATHWAYS: A normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it. The first findings in this area were made using haematopoietic stem cells (HSCs) and their transformed counterparts in leukemia . However, these pathways appear to be shared by stem cells of all organs. CSC- PATHWAYSCSC- PATHWAYS: Bmi-1 This group of transcriptional repressor was discovered as a common oncogene activated in lymphoma and later shown to specifically regulate HSCs and neural stem cells. This pathway appears to be active in CSC of pediatric brain tumors and CRC CSC- PATHWAYSCSC- PATHWAYS: Bmi-1 ** In normal cells BMI-1 inhibits the transcription of CDNK2A which encodes two cyclin dependent kinase inhibitors, INK4A and ARF. ** Cell cycle progression is promoted in the absence of INK4A and pro-apoptotic genes are inhibited in the absence of ARF. Hence, BMI-1 promotes proliferation and inhibits apoptosis. **In the case of cancer, BMI-1 is circumvented and CDNK2A is no longer inhibited, thereby resulting in unregulated proliferation and self-renewal. CSC- PATHWAYSCSC- PATHWAYS: Notch The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors . CSC- PATHWAYSCSC- PATHWAYS: Wnt/ β -catenine This pathway is strongly implicated as stem cell regulators. It is commonly hyperactivated in tumors and is required to sustain tumor growth. Their role has been illustrated especially in gliomas (the Gli transcription factors), CRC and mammary tumors. CSC- PATHWAYSThe Wnt-B-catenine pathway: In the normal Wnt pathway the levels of the transcription factor ß-catenin mediates self-renewal. ß-catenin could be turned off by a destruction complex as a feedback mechanism. However, in cancer the control process is circumvented and ß-catenin levels constantly thrive, hence causing continual proliferation and self- renewal. The Wnt-B-catenine pathwayCSCs in different solid tumors: Stem cells may cause some forms of bone cancer, University of Florida Osteosarcoma occurs right next to the most active centers of growth, the growth plates in long bones. These areas of the skeleton contain many stem cells undergoing rapid growth and developing into bone during the adolescent growth spurt. A stimulated, abnormal stem cell might therefore be the cell of origin of osteosarcoma . stem-like cells were isolated from tumors. About one in 1,000 cells in the samples had features of embryonic stem cells. The researchers also found abundant levels of the two key factors that help maintain embryonic stem cells in a very primitive state. CSCs in different solid tumorsThe Real Problem in Breast Tumors: Cancer Stem Cells: The Real Problem in Breast Tumors: Cancer Stem Cells At the University of Michigan researchers have identified a small population of cells in breast tumors that can seed the growth of new cancers. These cancer-causing cells, which make up a tiny fraction of cells within tumors, have properties similar to those of stem cells.CSCs in Colorectal carcinoma: CSCs in Colorectal carcinomaCSCs in Colorectal carcinoma: CSCs in Colorectal carcinomaCSCs in Hepatocellular carcinoma: CSCs in Hepatocellular carcinomaCSC hypothesis & Drug Resistance: The CSC hypothesis states: “the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance transporters. This resting constitutively drug-resistant cell remains at low frequency among a heterogeneous tumor mass. The mutation allows for unbridled cell growth and resistance to chemotherapeutic efforts since CSCs express genes for drug resistance and anti-apoptotic mechanism, . CSC hypothesis & Drug ResistanceCONCLUSION: Stem cells are immature cells that can replicate, or renew themselves, and are able to differentiate into all cells types. mutations and rearrangements of the genomes of stem cells give rise to CSCs. These changes could underlie the development of cancers in many tissues. Stem cells are more difficult to kill. Because they are so important throughout a person's lifetime, they have developed mechanisms that protect themselves. Therefore, tumor stem cells are able to resist toxic substances, such as cancer drugs. CONCLUSIONCONCLUSION: The next step is to figure out what makes the CSC different from the other cells in the tumor. DNA microarrays could be used to identify genes that are active in the cancer-causing cells (CSCs) compared to other tumor cells. Some of these genes might control the cell's ability to replicate and metastasize. Identifying these genes may suggest new drug targets that could selectively kill the cancer cells CONCLUSION You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.