EMT is the loss of membrane E-cadherin in adherent junctions, where β-catenin may play a significant role. Translocation of β-catenin from adherent junctions to the nucleus may lead to a loss of E-cadherin, and subsequently to EMT. There is evidence that nuclear β-catenin can transcriptionally activate EMT-associated target genes, such as the E-cadherin gene repressor SLUG (also known as SNAI2).
Recent data has supported the concept that tumor cells undergoing an EMT could be precursors for metastatic cancer cells, or even metastatic cancer stem cells. In the invasive edge of pancreatic carcinoma, a subset of CD133+CXCR4+ (receptor for CXCL12 chemokine also known as a SDF1 ligand) cells has been defined. These cells exhibit significantly stronger migratory activity than their counterpart CD133+CXCR4– cells, but both cell subsets show similar tumor development capacity. Moreover, inhibition of the CXCR4 receptor led to reduced metastatic potential without altering tumorigenic capacity.
On the other hand, in breast cancer, CD44+CD24– cells are detectable in metastatic pleural effusions. By contrast, an increased number of CD24+ cells have been identified in distant spread in patients with breast cancer. Although there are only few data on mechanisms mediating spread in breast cancer, it is possible that CD44+CD24– cells initially metastasize and in the new site change their phenotype and undergo limited differentiation. These findings led to a new dynamic two-phase expression pattern concept based on the existence of two forms of cancer stem cells: stationary cancer stem cells (SCS) and mobile cancer stem cells (MCS). SCS are embedded in tissue and persist in differentiated areas throughout all tumor progression. The term MCS describes cells that are located at the tumor–host interface. There is evidence that these cells are derived from SCS through the acquisition of transient EMT.
Multiple CSCs have been reported in prostate, lung, and many other organs, including liver, pancreas, kidney, and ovary. In prostate cancer, the tumor-initiating cells have been identified in CD44+ cell subset as CD44+α2β1+, TRA-1–60+CD151+CD166+, or ALDH+ cell populations. Markers for lung cancer stem cells have been reported, including CD133+, ALDH+, CD44+, and oncofetal protein 5T4+.
The existence of cancer stem cells has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies.
Normal somatic stem cells are naturally resistant to chemotherapeutic agents. They produce various pumps, such as multidrug-resistant (MDR) pump, that pump out drugs and DNA repair proteins. They also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). Cancer stem cells that develop from normal stem cells may also produce these proteins, which could increase their resistance toward chemotherapeutic agents. The surviving CSCs then repopulate the tumor, causing a relapse. By selectively targeting CSCs, it would be possible to treat patients with aggressive, nonresectable tumors, as well as preventing patients from metastasizing and relapsing. The hypothesis suggests that upon cancer stem cells’ elimination, cancer could regress due to differentiation and/or cell death.
A number of studies have investigated the possibility of identifying specific markers that may distinguish cancer stem cells from the bulk of the tumor (as well as from normal stem cells). Proteomic and genomic signatures of tumors are also being investigated. In 2009, scientists identified one compound, salinomycin, that selectively reduces the proportion of breast cancer stem cells in mice by more than 100-fold relative to Paclitaxel, a commonly used chemotherapeutic agent.
The cell surface receptor interleukin-3 receptor-alpha (CD123) was shown to be overexpressed on CD34+CD38– leukemic stem cells (LSCs) in acute myelogenous leukemia (AML), but not on normal CD34+CD38– bone marrow cells. Jin et al. then demonstrated that treating AML-engrafted NOD/SCID mice with a CD123-specific monoclonal antibody impaired LSCs homing to the bone marrow and reduced overall AML cell repopulation, including the proportion of LSCs in secondary mouse recipients.
Cancer Stem Cells and the Novel Treatments
The design of new drugs for the treatment of cancer stem cells requires an understanding of the cellular mechanisms regulating cell proliferation. The first advances in this area were made with hematopoietic stem cells (HSCs) and their transformed counterparts in leukemia. It is now becoming increasingly clear that stem cells of many organs share the same cellular pathways. Leukemias have often been a window into larger truths about cancer in general. Chemotherapy, for instance, was shown to be effective in leukemia well before it was used on solid tumors. The scientific and medical clarity offered by leukemia is due in large part to the ability of researchers and physicians to easily take blood samples and identify the various cellular components of the blood cancers.
In leukemia, the bone marrow or blood becomes glutted with immature blood cells (in acute leukemias) or more mature blood cells (in chronic leukemias). In the 1990s, leukemia researchers isolated a different subpopulation of leukemia cells: cells not by themselves clogging bone marrow or blood vessels, but which could transfer a leukemia from a sick mouse into a previously healthy one. The implication was that these cells were the critical stem cells that actually caused the leukemia and gave rise to all the other immature or mature blood cells that clinicians saw in the samples under their microscopes. Since that time, researchers have found similar CSCs in most kinds of solid tumors, including breast, bladder, colon, and liver cancer.
Additionally, a normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it or by inducing oncoprotein activity.
Bmi-1:
The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma and later shown to specifically regulate HSCs. The role of Bmi-1 has also been illustrated in neural stem cells. The pathway appears to be active in CSCs of pediatric brain tumors.
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 hematopoietic, neural, and mammary stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary and other tumors. A particular branch of the Notch signaling pathway that involves the transcription factor Hes3 has been shown to regulate a number of cultured cells with cancer stem cell characteristics obtained from glioblastoma patients.
Sonic Hedgehog and Wnt:
These developmental pathways are also strongly implicated as stem cell regulators. Both Sonic Hedgehog (SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand. This is a trend rather than a rule. For instance, in colon cancer, hedgehog signaling appears to antagonize Wnt. SHH blockers are available, such as cyclopamine.
The cancer stem cell hypothesis accounts for observed patterns of cancer recurrence and metastasis following an apparently successful therapeutic intervention. In clinical practice, however, some cancers prove quite aggressive and invasive, resisting chemotherapy or radiation even when administered at relatively early stages of tumor progression. These tumors have increased chances of spreading, making treatment more difficult and compromising quality of life. The presence of CSCs in some malignancies may account for some of these metastases. Some researchers have suggested that the tumor aggressiveness may correlate with the proportion of cancer stem cells within a corresponding tumor. In this scenario, less-aggressive cancers contain fewer CSCs and a greater proportion of therapy-sensitive non-CSCs.
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