Cancer stem cells

Malignancies appear to be maintained by stem cells which provide a mechanism for cell dormancy and development of heterogeneity within a specific tumor.

All cells can acquire, mutations, but without self renewal, they cannot become the roots of cancer.

Pre-cancer stem cells arise from clonal, mutated tissue stem cells that disrupt normal tissue homeostasis: hematopoietic stem cells, that regulate in pre-leukemic bone marrow disorders.

In Myelodyspl proliferative, neoplasms and myelodysplastic syndrome, pre-leukemic stem cells acquire resistance to apoptosis and programmed cell death, providing the assurance of longevity, and they can evade in an adaptive immune responses, leading to self renewal leukemic cells that fuel secondary resistance in secondary myelogenous leukemia.

Cancers arise in organs and tissues that contain cells with the ability, for the lifetime of the person, to replicate in order to maintain and replace cells that are lost during aging or damage.

Account for 1-5% of all tumor cells.

Such cells are responsible for continued growth and expansion of tumor cell populations.

CSCs are present in many myeloid leukemias and solid tumors, including breast cancer, colon cancer, squamous cell skin cancer and glioblastoma.

CSCs or capable of initiating and maintaining, and developing cancer growth.

Cancer cells are the longest living cells and many tissues and multiple mutations must accumulate in malignancy.

Adult stem cells are a small number of undifferentiated cells existing in organs that help replenish cells within that organ as a result of normal cell turnover or injury.
Biomarkers for CSC‘s are commonly identified by flow cytometry in single suspensions.
In solid tumor biopsies or resection samples, biomarkers can be measured using immunohistochemistry or reverse transcription polymerase chain reaction.
Leukemia stem cell biomarkers are primarily identified by using reverse transcriptase PCR.

Many cell surface biomarkers, such as CD44, CD133, and EpCAM, as well as the enzyme A LDH are established CSC biomarkers.

And example of adult stem cells would be stem cells in the crypts of the G.I. tract, they constantly regulate the renewal of the crypt lining is cells migrate toward the mucosa.

Self-renewal is achieved through symmetric cell division creating two identical daughter cells, whereas asymmetric division results in one daughter cell that preserves the stem cell identity, while the other becomes the proliferating progenitor of differentiated cell types.
There 6 major pathways that allow stemmess characteristics upon cells: hedgehog, JaK/STAT, Nanog,  P13K/AKT and W t/beta-catenin pathways.
These pathways confer the ability of cells to self renew into identical daughter cells, demonstrating immortality, as well as to differentiate into various types of cancer cells.
Some of these pathways also are involved in migration, resistance, and tumor initiation epithelial-mesenchymal transitions and mesenchymal epithelial transitions seen in metastases.
Embryonic and adult stem cells or phenotypically differentiate is their ability to unregulated, and primary symmetric, cell division.

The initial oncologic mutation probably occurs in stem cells.

May be key to the differences in the incidence of cancer in different organs.

Cancer arises from sequential mutations accumulating in tissue stem cells.

CSCs with self renewal capacity are responsible for developing functionally and morphologically diverse cells, including those that are therapy-resistant and metastatic cell populations.

Persistence of cancer stem cells is believed to be the ultimate cause of treatment failure or recurrence.

There is a close linear relationship between the number of stem cell divisions in tissues and the incidence of cancer in that organ.

Have the capacity to drive carcinogenesis by reduction and self renewal of differentiated, non-tumorigenic progenies.

Tissues and organs in which cancer commonly develop such as bone marrow, skin, mammary glands, gut, prostate gland, liver and even the brain contains stem cells.

Cancer cells use normal stem-sell self renewal for long-term proliferation and tissue repair pathways for invasion, suggesting that stem cell frequency in a cancer would correlate with prognosis which it does in breast cancer, colon cancer, and AML.

Stem cells persist for a lifetime, and can expand to regenerate themselves after the loss of stem cells because of exposure to toxins, and can migrate in the tissue to repair tissue injury.

Inflammation and activation of the innate immune system by toll-like receptor (TLR) signaling stem cells of the G.I. tract and mammary glands are activated by TLR to repair the tissue damage.

The stem cells in mammary glands, brain, and skin are mostly quiescent.

A large number of leucine-rich repeat containing G-proteins-coupled receptors 5 positive cells in the gut or actively proliferating.

Stem cells in different tissues are not identical.

Genes such as Nanog, Oct-4 and SOX-2 are responsible for the pluripotenial of cells, and are commonly considered surrogate markers for CSCs.

Nanog, a homeobox protein encoded by Nanog, a transcription factor and regulates stem cell properties, especially its self-renewal pluripotential.

Oct 4 contributes to the self renewal abilities and inhibits genes responsible for differentiation and self renewal of stem cells.

It is suspected that CSCs chemoradio resistant have a greater potential of tumor initiation and regrowth of cancer after therapy.

They have biological activity may contribute to initiation, maintenance, and relapse of some types of cancer.

These cells express drug transporters and components of DNA repair system and are refractory to programmed cell death.

Best characterized by acute myelogenous leukemia, where several studies have shown that such stem cells are refractory to commonly used clinical agents, indicating that the cells may represent a reservoir from which disease relapse may occur.

CSCs exhibit high invasive capacity, clonal evolution, dormancy, promote blood vessel proliferation, trigger cell mobility, promote tumorigenesis, promote tumorprogression and metastases.

CSCs had been harvested from virtually every major type of cancer.

Refers to a small group of cells within a tumor that appears to have tumor initiating abilities.
CSC‘s may be the cause of recurrence, they may promote resistance to treatment, and can contain the mechanisms necessary for metastases. 
Resistance mechanisms in CSC‘s include: increased expression of ABC transporters, maintenance of low reactive oxygen species levels, overexpression of anti-Apoptosis regulators to reduce apoptosis, activation of DNA repair systems, and activation of multiple stemnesspathways.
CSC‘s are integral part of all cancers and potentially present in all stages of a malignancy.

Hematopoietic cancer stem cells are featured by CD34 positive cells.

CSCs exists in many solid tumors including: Breast cancer, brain cancer, prostate cancer, melanoma, colon cancer, liver cancer, pancreatic cancer, and head and neck cancer.

In vitro CSCs grow as dimensional cellular aggregates known as spheroids, that range up to 300 µ in diameter.

CSCs from different cancers have different surface markers.

Breast cancer stem cells are CD 44 positive and CD 24 low.

CSCs resistant to conventional chemotherapy can remain in the dormant state, even when the majority of non-CSCs have been killed by therapy.

Fluorescein dye studies have demonstrated that self renewal of such cells is driven frequently by symmetric division instead of asymmetric division: Leading to the formation of 2 identical CSCs unlike the division in normal cells, and which is single division always results of the formation of the stem cell and a committed cell.

Cellular pathways that are involved with dormancy or growth patterns are the Hedgehog, Notch abd Wnt.

It is postulated that cancer stem cells are transformed normal stem cells, and that normal stem cells that exist in a wide spectrum of differentiated states may undergo a neoplastic genetic insult to become a cancer stem cell.

CSCs may be resistant to DNA damage by chemotherapy and to radiotherapy.

When not activated CSC‘s grow slowly and in their quiescent stage they are resistant to chemotherapy agents that target rapidly dividing cells.
The innate resistance of CSC‘s to antineoplastic therapy allows subsequent proliferation and the reestablishment of the tumor.

Reestablished lesions contain a much higher fraction of resistant CSCs that are much harder to treat.

Glioma CSCs are radio resistant, can amplify the rate of DNA repair following radiation-induced damage and following radiation exposure glioblastomas are enriched by CD 133+CSCs.

Cancer stems cells and normal stem cells can circulate, extravasate, invade, colonize normal tissues, regenerate and heal tissues and induce angiogenesis.

CSCs are enriched during invasion and metastases and the level of stem cell markers in the tumor or in metastatic sites, such as lymph nodes, correlates with tumor aggressiveness.

CSCs may contribute to tumor is heterogeneity and to vascular and stromal elements in the tumor’s microenvironment.

Stimulated CSCs respond to stimuli, proliferate, and reestablish the same histomorphology as the tumor of origin.

Recapitulated tumor stem cells express the same CD markers and have the same intracellular proteins as in normal stem cells of the same tissue.

HER2 amplification increases the numbers a cancer stem cells in tumor tissues.

Loss of the phosphatase and tensin homolog (PTEN) gene, a defect found in 40% of breast cancer patients increases the number of cancer stem cells.

In triple negative breast cancer, the claudin-low bone molecular subtype of breast cancer, a suggested as the most stem like tumor because of cancer stem cell-like features, such as CD 44 positive/CD 24 low phenotype.

Dysregulation of stemness pathways can explain complications seen in patients during their cancer including recurrence, resistance, and metastases.

Each CSC with the ability to self renew and differentiate can initiate a tumor iand establish a new lesion if the microenvironment is suitable.

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