Ovarian Cancer Spheroid Cells with Stem Cell-Like Properties Contribute to Tumor Generation, Metastasis and Chemotherapy Resistance through Hypoxia-Resistant Metabolism
TL;DR: In insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells, spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics and contributed to tumor generation, progression and chemotherapy resistance.
Abstract: Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >105 parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. 13C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.
Citations
More filters
TL;DR: This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids.
603 citations
Cites background from "Ovarian Cancer Spheroid Cells with ..."
...Additionally, increased resistance to chemotherapeutic drugs in spheroids may be attributed to activation of hypoxia resistant metabolic pathways, leading to enrichment of CSCs in spheroids (Liao et al., 2014)....
[...]
...Studies have indicated that tumor spheroids display significantly increased glucose consumption and lactate production compared to 2D-cultured cancer cells (Khaitan et al., 21 21 2006; Liao et al., 2014)....
[...]
Harvard University1, Linköping University2, University of California, San Diego3, University of North Carolina at Chapel Hill4, Emory University5, University of Bari6, Alderson Broaddus University7, Nara Medical University8, National Technical University of Athens9, Mayo Clinic10, University of Florence11, Cairo University12, United Arab Emirates University13, University of Illinois at Urbana–Champaign14, University of Rome Tor Vergata15, New York Medical College16, Purdue University17, Wayne State University18, University of Glasgow19, Karolinska Institutet20
TL;DR: 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy are identified and 10 plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity.
387 citations
TL;DR: Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets.
Abstract: Cancer is now viewed as a stem cell disease. There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. Cancer stem cells also seem to adapt their metabolism to microenvironmental changes by conveniently shifting energy production from one pathway to another, or by acquiring intermediate metabolic phenotypes. Determining the role of cancer stem cell metabolism in carcinogenesis has become a major focus in cancer research, and substantial efforts are conducted towards discovering clinical targets.
343 citations
TL;DR: A well-defined soluble basement membrane extract, termed BME/Matrigel, prepared from an epithelial tumor is similar in content to authentic basement membrane, and forms a hydrogel at 24-37°C and has widespread use in assays and in models that improve understanding of tumor biology and help define therapeutic approaches.
338 citations
TL;DR: This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.
Abstract: A class of near-infrared fluorescence (NIRF) heptamethine cyanine dyes that are taken up and accumulated specifically in cancer cells without chemical conjugation have recently emerged as promising tools for tumor imaging and targeting. In addition to their fluorescence and nuclear imaging-based tumor-imaging properties, these dyes can be developed as drug carriers to safely deliver chemotherapy drugs to tumors. They can also be used as effective agents for photodynamic therapy with remarkable tumoricidal activity via photodependent cytotoxic activity. The preferential uptake of dyes into cancer but not normal cells is co-operatively mediated by the prevailing activation of a group of organic anion-transporting polypeptides on cancer cell membranes, as well as tumor hypoxia and increased mitochondrial membrane potential in cancer cells. Such mechanistic explorations have greatly advanced the current application and future development of NIRF dyes and their derivatives as anticancer theranostic agents. This review summarizes current knowledge and emerging advances in NIRF dyes, including molecular characterization, photophysical properties, multimodal development and uptake mechanisms, and their growing potential for preclinical and clinical use.
194 citations
References
More filters
10,654 citations
TL;DR: The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival and strategies designed to target this population may lead to more effective therapies.
Abstract: Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.
10,058 citations
"Ovarian Cancer Spheroid Cells with ..." refers background or result in this paper
...We examined whether exponentially smaller numbers (compared with parental cancer cells) were capable of tumorigenesis, as previously shown for other epithelial cancer initiating cells (CICs) [24–28]....
[...]
...The median tumor latency time in this cohort was 31 to 90 days for RP-OV17534 spheroid and 50 to 57 for OV2774 spheroid, similar to or less than CICs of other malignancies [24–27]....
[...]
TL;DR: The most recent data on cancer incidence, mortality, and survival from the American Cancer Society (ACS) is presented in this paper, where the authors compare the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancers sites in women (breast and colorectal) over a 15-year period.
Abstract: Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
9,129 citations
01 Jan 1956
8,572 citations
"Ovarian Cancer Spheroid Cells with ..." refers background in this paper
...Cancer cells adopt an alternative metabolic pathway and increase their glycolytic activity through a process called the Warburg effect [41]....
[...]
TL;DR: It is shown that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties and these cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model.
3,766 citations
"Ovarian Cancer Spheroid Cells with ..." refers background in this paper
...Recent studies show that increased ALDH activity leads to several types of malignancies, serves as a cancer stem cell marker and correlated with poor prognosis [36–39]....
[...]