Proliferative tissues such as skin and bone marrow are maintained by a stable population of progenitor cells with self-renewing properties. Tumors are also proliferative tissues, possibly maintained by a self-renewing cancer stem cell population. Therefore leukemia can be viewed as a tumor maintained by a subset of bone marrow progenitor cells that have tumor-initiating properties. Analogously, mesothelioma may be a tumor maintained by a mesothelial progenitor cell population. Normal mesothelium consists of a single layer of simple squamous mesothelial cells of mesodermal origin that function to maintain serosal fluid production in order to provide a frictionless and protective surface for organ movement.
Mesothelial cells also participate in material transport across the serosal membrane; and mediate regulatory inflammatory, immune, and tissue repair responses (Mutsaers, 2007). There is evidence for a mesothelial progenitor cell population (Herrick, 2004). First, mesothelial cells express characteristics of mesodermal, epithelial and mesenchymal phenotypes- supportive evidence for multipotential differentiation of a progenitor cell population. In addition, mesothelial cells exhibit plasticity by transforming into tissues such as myofibroblasts and vascular grafts under specific growth conditions (Lv, 2011 & Sparks, 2002).
After mesothelial tissue injury, new mesothelium regenerates from both cells at the wound edge and from the surrounding serosal fluid, which may be mesothelial progenitor cells capable of tissue regeneration. Mesothelial progenitor cells with such stem cell-like properties are potentially a source of a cancer stem cell population in mesothelioma. Another potential cancer stem cell population in mesothelioma is side population (SP) cells. Defined as cells that efflux the DNA-binding dye Hoechst 33342, SP cells can be enriched for using flow cytometry. Side population cells express ATP-binding cassette (ABC) membrane transporters that efflux the Hoechst 33342 dye, and these transporters are also involved in efflux of drugs such as chemotherapeutic.
Side population cells are found in both normal and malignant tissues. In cancer, SP cells have been considered a potential cancer stem cell population as well as a cell population responsible for resistance to therapy. SP cells have been identified as a potential cancer stem cell population in various tumors, including ovarian carcinoma and osteosarcoma (Fong, 2010 & Murase, 2009). A group that isolated SP cells from human malignant mesothelioma cell lines illustrated that SP cells had enhanced proliferation and higher expression of stem-cell genes (Kiyonori, 2010). However, the SP cells did not have increased tumorigenic potential in immunodeficiant mice.
A more recent study reported that SP cells isolated from malignant pleural mesothelioma not only expressed stem cell markers, but also showed self-renewal, chemoresistance, and tumorigenicity (Frei, 2011). Further the subset of SP cells characterized as WT1 negative/D2- 40 positive/CD105 (low) were found to be even more tumorigenic. The increased stem cellness of the SP cells isolated from this study by Frei et al. compared to the study by Kiyonori et al. could be due to their isolation from malignant tissue rather than from mesothelioma cell lines.
Since cancer stem cells remain to be fully characterized and defined, a diversity of cell types- including progenitor cells and side population cells- may qualify as cancer stem cells in tumors (Bjerkvig, 2005). How a normal mesothelial progenitor cell or side population cell transforms into a cancer stem cell remains to be elucidated.
Traditional thinking of transformation of a normal differentiated cell into a tumor cell requires multiple hits to the genome resulting in genetic instability and a selective survival advantage. Cancer stem cells may be products of a similar transformative process. Human mesothelial cells exposed to asbestos and SV40 virus were reported to transform via an Akt-mediated cell survival mechanism (Cacciotti, 2005). These authors concluded that mesothelioma originates from a subpopulation of transformed stem cells.
More work illustrating this important concept is necessary and offers potential targets for therapy to abrogate this transformation process. Hypothetically, the advantage for a tumor to arise from a transformed stem cell rather than from a transformed differentiated cell includes the ability for the tumor to have multiple phenotypes for growth in different microenvironments; an additional mechanism for a metastatic phenotype; and resistance to current therapies. Interestingly, mesothelioma exhibits aspects of all three of these tumor characteristics. Diffuse malignant mesothelioma can be classified histologically into three major classes: epithelioid, sarcomatoid, and mixed-type. Epithelioid is the most common phenotype and the mixed-type can be found in 30% of tumors.
Sarcomatoid tumors are rare but carry the worst prognosis. There are also rare variants including desmoplastic, undifferentiated and deciduoid types. This wide variety of phenotypes could be explained by a cancer stem cell origin for mesothelioma, such as a transformed mesothelial progenitor cell population that has been shown to differentiate into multiple cell types. Currently, determining the histological subtype is important for diagnosis, prognosis and treatment (Tischoff, 2011).
If, however, all the histological subtypes are derived from a single stem cell population, earlier diagnosis could be determined before histological differentiation occurs; prognosis could be improved overall; and treatment could be focused on targeting these stem cells. Mesothelioma is an aggressive tumor that often metastasizes. In tumor biology epithelialmesenchymal transition (EMT) is associated with increased tumor invasiveness and metastasis. This transition is reminiscent of the epithelioid versus sarcomatoid type of mesothelioma, and therefore has important implications in the metastastic feature of this tumor.
EMT is a transdifferentiation program used in normal embryonic development. Activation of this program in carcinogenesis would confer a metastatic phenotype to the tumor cells. Not only can EMT increase cell invasiveness and migration, but it also contributes to additional properties that promote tumor cell survival; such as resistance to apoptosis and senescence, and increased immunosuppression (Thiery, 2009).
In addition, EMT has been shown to induce stem cell-like properties. Many cancer stem cell traits are consistent with a metastatic phenotype- self-renewal, ability to initiate tumors in a new environment, motility, invasiveness, and resistance to apoptosis (Chaffer, 2011). Evidence of EMT occurring in mesothelioma includes expression of proteins involved in the EMT axis in malignant pleural mesothelioma tissue samples from untreated patients, and expression of the periostin protein in particular by sarcomatoid tumors, which in turn correlated with shorter survival in these patients (Schramm, 2010).
Successful colonization of metastatic cells to the distant tissues requires activation of genetic and epigenetic programming for survival in the new tissue environment. This area of research is relatively new, but it is believed that the self-renewal property of stem cells offers one explanation for homing success. Once in the new microenvironment, metastatic cells need to successfully utilize the local growth factors and cytokines to gain mitogenic potential and the ability to self-renew. Subsequently the metastatic cells would need to recruit the stroma to aid in cell survival, such as inducing a blood supply (Chambers, 2002).
Distant metastatic lesions of mesothelioma, amongst other tumors both epithelial and nonepithelial, have been reported to highly express the self-renewal gene Bmi-1, suggesting that a state of self-renewal is linked to metastatic potential (Glinsky, 2005). Whether the metastatic cells in mesothelioma represent a cancer stem cell population derived from the primary tumor, or mesothelioma cells that acquired stem cell-like properties such as selfrenewal en route to and after homing to the distant metastatic site, remains to be studied. However these finding support a role for stem cells in the pathogenesis of mesothelioma.
Epigenetic mechanisms that do not change the DNA sequence but that do alter gene expression at the mRNA and protein levels are exciting new potential targets for therapy. A number of epigenetic mechanisms have been described in tumors, including microRNA (miRNA) regulation of mRNA expression, histone acetylation/deacetylation, and gene promoter methylation/demethylation. By suppressing expression of tumor suppressor genes or increasing expression of oncogenes, these epigenetic proteins regulate tumorigenesis at an additional level of complexity.
A study identifying a panel of miRNAs downregulated in malignant pleural mesothelioma tissue samples found redundant miRNA regulators of Wnt signaling, an important pathway in stem cell self renewal (Gee, 2010). Wnt signaling in mesothelioma suggests a cell population with stemness properties, and whose expression appears to be regulated at an epigenetic level. The existence of a cancer stem cell population in mesothelioma is supported by evidence of cells with stem cell-like properties in normal mesothelium, primary mesothelial tumors, and metastatic lesions.
A definitive cancer stem cell population capable of re-initiating mesotheliomal tumors remains to be identified. If such a cancer stem cell population is discovered, the prospects of earlier diagnosis and novel therapy for malignant mesothelioma would be of utmost importance for further research.
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