STEM CELLS IN SOLID TUMORS CANCER STEM CELL (CSC

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What are stem cells?
cells are unspecialized immature cells that can renew themselves through cell division for long periods of time. time.
** They are necessary for our survival. Skin stem cells renew survival.
** Stem

and repair our skin. Cells in our bone marrow generate the skin. different cell types in our blood. 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 differentiation:
cells« cells« etc ** The blood system has the best described normal stem

cells. cells.

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** For research purposes. ovum.Types of stem cells Embryonic stem cells (pluripotent): (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. 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 cells Adult stem cells (multipotent stem cells): 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 .

Alzheimer¶s. cell therapy.How can stem cells be used to treat diseases? Stem cells as ³REPLACEMENT PARTS´: A wide range of diseases (heart disease. Parkinson¶s. diabetes.) may be amenable to stem etc. Ex. appropriate place in the body and become the appropriate cell type. Stem cells were directed to the therapy. etc. motor neuron disease. stem cells could be made to migrate to an injured spinal cord and become nerve cells to cure paralysis . type. Ex.

disease. The stem cells can be made to generate the cell type that is defective in that disease. disease. disease.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. We can also use these cells to test drugs that might block the progression of the disease . we can gain insight into what goes wrong at the molecular level in the disease. By studying these cells.

1950. and the disease only manifests if its control (immune response and nutrition) nutrition) are impeded. . It states that cancer--differentiated cancer--differentiated trophoblast proliferation-. impeded.is part of the proliferation-healing process.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.

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. disease. . 3) Cancer is a proliferative disease.Cancer stem cell theory There are two competing visions of tumors. tumorigenic. death. Old cancer model: 1) All tumor cells can form new tumors and are therefore equally tumorigenic.

3) Cancer is a stem cell disorder and not a simple mechanism whereby cell proliferation is disrupted.Cancer stem cell theory New cancer model: 1) Tumors arise from cells termed cancer stem cells that have properties of normal stem cells. disrupted. . particularly selfselfrenewal and multipotentiality (a minority) of tumor cells. 2) Unregulated cell growth is due to a disruption in the regulatory mechanism in stem cell renewal. cells. renewal.

This theory explains why are many cancers so difficult to treat. metastasis. treat.   .Cancer stem cell theory These CSCs cells persist in tumors as a distinct population that likely causes relapses and metastasis.

Cancer 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 longacquire the necessary number of sequential mutations to convert a normal cell into a malignant one. one. .

  . especially for sufferers of metastatic disease. remains untouched and may cause a relapse of the disease. which form the bulk of the tumor but are unable to generate a new one. Development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients. A population of CSCs. disease. which gave rise to it. where little progress has been made in recent years. one. disease. years.Are we targeting the right cells?  Conventional chemotherapies kill differentiated or differentiating cells.

.WRONG TARGET. killing cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance. In theory. Traditional cancer therapies (top) kill rapidly dividing tumor cells (blue) but may spare stem cells (yellow) that can give rise to a new tumor.

What are Cancer Stem Cells? Cells that have properties of normal stem cells: cells: self-renew. types. 3) They form a distinct population in tumors that likely causes disease relapse and metastasis. metastasis. . 2) Tha ability to differentiate into multiple cell types. 1) The abilities to self-renew.

SelfSelf-renewal of stem cells The concept of selfselfrenewal is crucial to understand CSC. treatments. and also to get insight on the mechanism by which current therapies might evade the available treatments. .

time. 2) The doubling time of most stem cells is relatively long. cell. 3) In some stem cells at division the `mother¶ cell retain the original chromosome while providing the daughter with the newly formed chromosome (Chromosomal minimizes mutation in the mother preservation) cell. . damage). compared to their immediate progenitors. as long. which replicate with shorter doubling times (Repair of DNA damage).SelfSelf-renewal of stem cells 1) Provides the cell with the ability to undergo infinite cellular divisions with only few of the stem cells dividing at a particular time.

cells. or cancer cells.CSC 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. . also referred as malignant cells or transformed cells.

The decades. diseases. mutations are thought to promote the tumor stem cells' ability to proliferate. 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. eventually leading to cancer   .Normal Stem Cells vs. But they develop because of mutations that accumulate over years and often decades.

Animal research. establish a tumor. ** The critical importance of the microenvironment.Evidence for the presence of CSC 1) In exp. ** The particular biochemical surroundings of the injected cells.000. have CSC. In human AML the tumor. frequency of these cells is less than 1 in 10. microenvironment.000. the CSC. by: ** Poor methodology (loos of cell viability during transfer). efficient tumor formation to exp. transfer). the potential to generate a tumor. . This was formerly explained by: tumor. According to CSC theory only a small fraction of the injected cells. cells. 10.

cells. a classical hallmark of stem cells. metastases. . This implies that the cell that produced them had the capacity to generate multiple cell types (have a multidifferentiative potential). potential).Evidence for cancer stem cells 2) Tumor heterogeneity: Most umors are heterogeneity: very heterogeneous and heterogeneity is commonly retained by tumor metastases.

these pathways appear to be shared by stem cells of all organs. However. transformed counterparts in leukemia. .PATHWAYS    A normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it.CSCCSC. The first findings in this area were made using haematopoietic stem cells (HSCs) and their leukemia. it. organs.

This pathway appears to be cells.PATHWAYS BmiBmi-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. active in CSC of pediatric brain tumors and CRC .CSCCSC.

apoptosis. ** Cell cycle progression is promoted in the absence of INK4 INK4A and pro-apoptotic genes are inhibited in the proabsence of ARF. INK4 ARF. Hence. thereby resulting in unregulated proliferation and self-renewal. BMIand inhibits apoptosis.CSCCSC. BMI-1 is circumvented and BMICDNK2 CDNK2A is no longer inhibited. INK4A and ARF. BMI-1 promotes proliferation ARF.PATHWAYS BmiBmi-1 ** In normal cells BMI-1 inhibits the transcription of BMI- CDNK2 CDNK2A which encodes two cyclin dependent kinase inhibitors. . **In the case of cancer. self-renewal.

decades. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors. neural and mammary stem cells.   . tumors.CSCCSC. cells.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.

CRC and mammary tumors.CSCCSC. Their role has been illustrated especially in gliomas (the Gli transcription factors). It is commonly hyperactivated in tumors and is required to sustain tumor growth.PATHWAYS Wnt/ -catenine  This pathway is strongly implicated as stem cell regulators. tumors. growth. regulators.   .

mechanism. self.   .The Wnt-B-catenine Wntpathway  In the normal Wnt pathway the levels of the transcription factor ß-catenin mediates selfselfrenewal. However. hence causing continual proliferation and self.renewal. ß-catenin could be turned off by a destruction complex as a feedback mechanism.renewal. in cancer the control process is circumvented and ß-catenin levels constantly thrive. renewal.

The Wnt-B-catenine pathway Wnt- .

stemstem-like cells were isolated from tumors. University of Florida  Osteosarcoma occurs right next to the most active centers of growth. osteosarcoma. the growth plates in long bones. About one in 1. spurt. A stimulated. found abundant levels of the two key factors that help maintain embryonic stem cells in a very primitive state. The researchers also cells.    . abnormal stem cell might therefore be the cell of origin of osteosarcoma.000 cells in tumors. These areas of the skeleton contain many stem cells undergoing rapid growth and developing into bone during the adolescent growth spurt. state. bones. the samples had features of embryonic stem cells.CSCs in different solid tumors Stem cells may cause some forms of bone cancer.

have properties similar to those of stem cells. cancers. These cancercancercausing cells. which make up a tiny fraction of cells within tumors. 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.

CSCs in Colorectal carcinoma .

CSCs in Colorectal carcinoma .

CSCs in Hepatocellular carcinoma .

The mutation allows for unbridled cell growth and resistance to chemotherapeutic efforts since CSCs express genes for drug resistance and anti-apoptotic antimechanism. . which retains the selfessential property of self-protection through the activity of multiple drug resistance transporters. This resting constitutively drug-resistant cell remains drugmass. at low frequency among a heterogeneous tumor mass.CSC hypothesis & Drug Resistance  The CSC hypothesis states: ³the cancer-initiating cell states: canceris a transformed tissue stem cell.   . transporters.

so important throughout a person's lifetime. types. such as cancer drugs. Therefore. These changes could CSCs. Stem cells are more difficult to kill.CONCLUSION  Stem cells are immature cells that can replicate. themselves. or renew themselves. mutations and rearrangements of the genomes of stem cells give rise to CSCs. drugs. underlie the development of cancers in many tissues. Because they are kill. and are able to differentiate into all cells types. they have developed mechanisms that protect themselves. tissues. tumor stem cells are able to resist toxic substances.   .

tumor.CONCLUSION  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) cancercompared to other tumor cells. Some of these genes cells. metastasize. Identifying these genes may suggest new drug targets that could selectively kill the cancer cells   . might control the cell's ability to replicate and metastasize.

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