Ovarian Cancers Evolving Paradigms in Research and Care (2016) / Chapter Skim
Currently Skimming:
2 The Biology of Ovarian Cancers
2 The Biology of Ovarian Cancers
Pages 57-96
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From page 57... ...
Ovarian cancer can arise from any of these cell types, but ovarian carcinomas (cancers with epithelial differentiation) make up the majority of ovarian cancers and are responsible for most ovarian cancer–related deaths (Kurman, 2013)
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, EC is one of the two major types of ovarian carcinoma with a well-defined association with endometriosis (ectopic endometrial tissue) (DePriest et al., 1992; Erzen et al., 2001; Yoshikawa et al., 2000)
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Metastases from LGSCs often manifest as small solid nests of tumor cells or as micropapillae surrounded by clear spaces or clefts that invade haphazardly into involved tissue. Despite the similarity in names, LGSCs infrequently progress to HGSCs, and, for the most part, the two types of ovarian carcinomas have non-overlapping mutational patterns (Vang et al., 2009)
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Ovarian Carcinoma Classification and Nomenclature The classification and nomenclature of ovarian carcinomas has evolved over many decades and may continue to evolve as the understanding of the carcinomas' origin and molecular features becomes more refined. Historically, more than one term has been used for some ovarian carcinoma types, which may have hindered progress in understanding their biology and clini
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In fact, detecting ovarian cancers early may require looking in locations other than the ovaries themselves, because a growing evidence base suggests that many ovarian carcinomas arise from sites outside the ovaries and spread to the ovaries secondarily. The Origins of HGSCs Historically, researchers and clinicians assumed that ovarian carcinomas develop from the ovarian surface epithelium (OSE)
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62 FIGURE 2-1 Potential cellular origins of ovarian carcinomas. NOTES: Data suggest that many ovarian carcinomas may originate from outside the ovaries.
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. Recent work done in a mouse model suggests that ovarian carcinomas may arise from a susceptible population of cells with stem cell–like properties that are present where the OSE, FTE, and peritoneal mesothelium converge (Flesken-Nikitin et al., 2013; Ng and Barker, 2015)
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. The shared mutational spectrum of endometriosis-associated ovarian cancers and uterine ECs suggests a common origin, likely attributable to endometriosis.
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. Implications In summary, only a small fraction of ovarian carcinomas may actually originate in the ovaries, and in response to that understanding, a paradigm shift is occurring that is moving the focus away from seeing the ovaries as the source of most ovarian carcinomas (Kuhn et al., 2012)
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or promote (oncogenes) the growth of ovarian carcinomas.
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This gene growth, and migration is often mutated in cancer • PPP2R1A: regulates signaling pathways that inhibit cell growth and division CCC • KRAS • ARID1A • PIK3CA • PTEN • PPP2R1A • TP53 NOTE: The descriptions describe the functions of the proteins encoded by the genes listed above. SOURCES: Anglesio et al., 2013a; Belanger et al., 2015; Cancer Genome Atlas Research Network, 2011; Della Pepa et al., 2015; Garrett et al., 2001; Gemignani et al., 2003; Jones et al., 2010; McConechy et al., 2011, 2014; Merritt and Cramer, 2010; Ryland et al., 2015; I
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. Some of the previous genetic studies of serous carcinoma have been confounded by the inclusion of other, non-serous subtypes of ovarian carcinoma.
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, long noncoding RNA, and small RNA transcripts from DNA -- in a cell or tissue. Historically, the study of tumor-specific alterations to DNA represented the major focus in cancer research.
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TUMOR HETEROGENEITY Ovarian cancers are heterogeneous tumors that can change in various ways as the disease progresses. Only a few small studies have investigated these variations in a comprehensive manner.
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However, most cancers other than ovarian cancer have a variety of treatment options available to overcome resistance when a specific therapeutic is no longer effective. Ovarian cancer is hindered by the lack of additional therapeutic options, and therefore an improved understanding of the molecular mechanisms underlying drug resistance in ovarian carcinomas could be useful for devising new targeted therapeutic approaches to overcome or bypass resistance.
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From page 72... ...
The use of different drugs with non-overlapping mechanisms of action may also be an important approach to overcoming platinum and other types of drug resistance. TUMOR MICROENVIRONMENT Cancers form because of a series of mutations in oncogenes or tumor suppressor genes, but the specific tumor microenvironment can shape the transcriptional and functional diversity of the resulting cancer cells ( belson et al., 2013; Cancer Genome Atlas Research Network, 2011; A Hanahan and Weinberg, 2011; Myers et al., 2006; Schwarz et al., 2015; Tlsty and Coussens, 2006; Touboul et al., 2014)
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The Role of the Immune System in Ovarian Cancers Cancer cells evade immunological elimination by inducing the expression of T cell inhibitory receptors on tumor cells and immune cells and by recruiting immunosuppressive cells such as regulatory T cells and tumor
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. For example, metastatic ovarian carcinomas typically seed into the adipose tissue of the peritoneum, which results in the reprogramming of adipocytes to generate free fatty acids that are then used by the cancer cells to generate ATP.
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These cells may mediate tumor metastasis and, by virtue of their relative resistance to chemotherapy and radiotherapy, may contribute to the treatment resistance commonly seen in ovarian cancers (Zhang et al., 2008)
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Cell Culture Models Cancer cell lines are the most commonly used models in cancer research, and their use has advanced the understanding of cancer biology. However, because of the heterogeneity and the distinct molecular features of different ovarian carcinomas, not all ovarian cancer cell lines are representative of all ovarian cancers (see Table 2-2)
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From page 77... ...
tion, drug response, phenotypic heterogeneity, and changes in gene expression and cell behavior. A human fallopian tube co-culture system of both secretory and ciliated cells was developed from primary human surgical specimens (Fotheringham et al., 2011; Levanon et al., 2010)
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A number of GEMMs developed over the past several years are outlined in Table 2-3; no GEMM of mucinous ovarian carcinoma has yet been reported. Developing an ovarian cancer GEMM requires being able to modify the genes of interest in the cells of interest.
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• More research is needed to determine the sites of origin and the pathogenesis of each subtype because current evidence suggests that only a fraction of ovarian carcinomas originate in the ovaries. • More research is needed to better understand the multitude of ge netic alterations that characterize ovarian cancers in order to help
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Pten; Dicer ± MISIIR(Amhr2) -Cre FTE and Tumors with Pten and Dicer inactivation initiate in fallopian tube Kim et al., 2012, Trp53 OSE stroma.
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-Cre OSE Fan et al., 2009 Pten; KrasG12D MISIIR(Amhr2) -Cre OSE Mullany et al., 2011 ENDOMETRIOID CARCINOMA MODELS Pten; Arid1a AdCre into bursa OSE Endometrioid and/or undifferentiated carcinomas arise in Guan et al., 2014 ~60 percent of mice within 6 months and in ~80 percent of mice within 8–9 months Pten; Apc ± AdCre into bursa OSE Tumor phenotype is more aggressive with mutant Pik3ca or Trp53 Wu et al., 2013 Pik3caE545K or Trp53 Pten; Apc ± AdCre into bursa OSE Tumor phenotype is less aggressive and tumors display more Zhai et al., 2015 Arid1a epithelial differentiation with Arid1a loss Pten; MISIIR(Amhr2)
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2013. Ovarian surface epithelium as a source of ovarian cancers: Unwarranted speculation or evidence-based hypothesis?
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2013. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial muta tional profiling.
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2010. Genomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma.
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: An entity distinct from other ovarian carcinomas as sug gested by a nested case-control study. Gynecologic Oncology 83(1)
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2006. Ovarian cancer cells polarize macrophages toward a tumor associated phenotype.
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2012. High grade serous ovarian cancer arises from fallopian tube in a mouse model.
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2007. Tumor irradiation increases the recruit ment of circulating mesenchymal stem cells into the tumor microenvironment.
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2011. Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas.
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2014. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer.
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2003. BRCA1/2-related ovarian cancers are of tubal origin: A hypothesis.
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2014. A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
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Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells and Development 21(14)
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2014. Reversing platinum resistance in high grade serous ovarian carcinoma: Targeting BRCA and the homologous recombination system.
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2001. Simul taneously detected endometrial and ovarian carcinomas -- A prospective clinicopatho logic study of 74 cases: A Gynecologic Oncology Group Study.
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