Advanced cases of epithelial ovarian, primary peritoneal, and primary tubal malignancies have a relatively poor prognosis and collectively remain the most deadly of all gynecologic malignancies. ...Although traditionally thought of as one disease process, ongoing research suggests that there is not 1 single site or cell type from which these cancers arise. A majority of the serous tumors appear to originate from dysplastic lesions in the distal fallopian tube. Therefore, what we have traditionally considered “ovarian” cancer may in fact be tubal in origin. In this article, we will review epithelial ovarian cancer classification and genetics, theories regarding cells of origin with a focus on tubal intraepithelial carcinoma, and implications for prevention and screening.
Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel ...most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression.
Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great deal has been learned about proteins and pathways important in the early stages of malignant transformation ...and metastasis, as derived from studies of individual tumors, microarray data, animal models, and inherited disorders that confer susceptibility. However, a full understanding of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lack of a well-defined premalignant state common to all ovarian subtypes and by the paucity of data from early-stage cancers. Evidence suggests that ovarian cancers can progress both through a stepwise mutation process (low-grade pathway) and through greater genetic instability that leads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In this review, we discuss many of the genetic and molecular disorders in each key process that is altered in cancer cells, and we present a model of ovarian pathogenesis that incorporates the role of tumor cell mutations and factors in the host microenvironment important to tumor initiation and progression.
Inducing destruction of specific mRNA using small interfering RNA (siRNA) is a powerful tool in analysis of protein function, but its use as a therapeutic modality has been limited by inefficient or ...impractical delivery systems. We have used siRNA incorporated into the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) for efficient in vivo siRNA delivery. In nude mice bearing i.p. ovarian tumors, nonsilencing siRNA tagged with the fluorochrome Alexa 555 was encapsulated into DOPC liposomes and shown to be taken up by the tumor as well as many major organs. Furthermore, DOPC-encapsulated siRNA targeting the oncoprotein EphA2 was highly effective in reducing in vivo EphA2 expression 48 hours after a single dose as measured by both Western blot and immunohistochemistry. Therapy experiments in an orthotopic mouse model of ovarian cancer were initiated 1 week after injection of either HeyA8 or SKOV3ip1 cell lines. Three weeks of treatment with EphA2-targeting siRNA-DOPC (150 microg/kg twice weekly) reduced tumor growth when compared with a nonsilencing siRNA (SKOV3ip1: 0.35 versus 0.70 g; P = 0.020; HeyA8: 0.98 versus 1.51 g; P = 0.16). When EphA2-targeting siRNA-DOPC was combined with paclitaxel, tumor growth was dramatically reduced compared with treatment with paclitaxel and a nonsilencing siRNA (SKOV3ip1: 0.04 versus 0.22 g; P < 0.001; HeyA8: 0.21 versus 0.84 g; P = 0.0027). These studies show the feasibility of siRNA as a clinically applicable therapeutic modality.
Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. One of the leading causes of death in high-grade serous ovarian cancer (HGSOC) is ...chemoresistant disease, which may present as intrinsic or acquired resistance to therapies. Here we discuss some of the known molecular mechanisms of chemoresistance that have been exhaustively investigated in chemoresistant ovarian cancer, including drug efflux pump multidrug resistance protein 1 (MDR1), the epithelial-mesenchymal transition, DNA damage and repair capacity. We also discuss novel therapeutics that may address some of the challenges in bringing approaches that target chemoresistant processes from bench to bedside. Some of these new therapies include novel drug delivery systems, targets that may halt adaptive changes in the tumor, exploitation of tumor mutations that leave cancer cells vulnerable to irreversible damage, and novel drugs that target ribosomal biogenesis, a process that may be uniquely different in cancer versus non-cancerous cells. Each of these approaches, or a combination of them, may provide a greater number of positive outcomes for a broader population of HGSOC patients.
Ovarian cancer is the fifth most common cause of death due to cancer in women despite being the tenth in incidence. Unfortunately, the five-year survival rate is only 45%, which has not improved much ...in the past 30 years. Even though the majority of women have successful initial therapy, the low rate of survival is due to the eventual recurrence and succumbing to their disease. With the recent release of the Cancer Genome Atlas for ovarian cancer, it was shown that the PI3K/AKT/mTOR pathway was one of the most frequently mutated or altered pathways in patients' tumors. Researching how the PI3K/AKT/mTOR pathway affects the progression and tumorigensis of ovarian cancer will hopefully lead to new therapies that will increase survival for women. This review focuses on recent research on the PI3K/AKT/mTOR pathway and its role in the progression and tumorigensis of ovarian cancer.
Purpose: Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic
cascade. Based on encouraging in vitro results with FAK silencing, we ...examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl- sn -glycero-3-phosphatidylcholine (DOPC).
Experimental Design: Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8,
and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments
of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl
transferase–mediated dUTP nick end labeling) were done using immunohistochemical analysis.
Results: A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started
1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 μg/kg twice weekly) reduced mean tumor
weight by 44% to 72% in the three cell lines compared with the control group ( P s < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction
in mean tumor weight in all models (all P s < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted
in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9,
and increased apoptosis of tumor-associated endothelial cells and tumor cells.
Conclusions: Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach
against ovarian cancer.
Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these ...populations are more capable of surviving chemotherapy in de novo tumors is unknown.
We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry. Tumors collected immediately after completion of primary therapy were then laser capture microdissected and subjected to a quantitative PCR array examining stem cell biology pathways (Hedgehog, Notch, TGF-β, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation.
Primary samples were composed of low densities of ALDH1A1, CD44, and CD133. Tumors collected immediately after primary therapy were more densely composed of each marker, whereas samples collected at first recurrence, before initiating secondary therapy, were composed of similar percentages of each marker as their primary tumor. In tumors collected from recurrent platinum-resistant patients, only CD133 was significantly increased. Of stem cell pathway members examined, 14% were significantly overexpressed in recurrent compared with matched primary tumors. Knockdown of genes of interest, including endoglin/CD105 and the hedgehog mediators Gli1 and Gli2, led to decreased ovarian cancer cell viability, with Gli2 showing a novel contribution to cisplatin resistance.
These data indicate that ovarian tumors are enriched with CSCs and stem cell pathway mediators, especially at the completion of primary therapy. This suggests that stem cell subpopulations contribute to tumor chemoresistance and ultimately recurrent disease.
Aldehyde dehydrogenase-1A1 (ALDH1A1) expression characterizes a subpopulation of cells with tumor-initiating or cancer stem cell properties in several malignancies. Our goal was to characterize the ...phenotype of ALDH1A1-positive ovarian cancer cells and examine the biological effects of ALDH1A1 gene silencing. In our analysis of multiple ovarian cancer cell lines, we found that ALDH1A1 expression and activity was significantly higher in taxane- and platinum-resistant cell lines. In patient samples, 72.9% of ovarian cancers had ALDH1A1 expression in which the percentage of ALDH1A1-positive cells correlated negatively with progression-free survival (6.05 vs. 13.81 months; P < 0.035). Subpopulations of A2780cp20 cells with ALDH1A1 activity were isolated for orthotopic tumor-initiating studies, where tumorigenicity was approximately 50-fold higher with ALDH1A1-positive cells. Interestingly, tumors derived from ALDH1A1-positive cells gave rise to both ALDH1A1-positive and ALDH1A1-negative populations, but ALDH1A1-negative cells could not generate ALDH1A1-positive cells. In an in vivo orthotopic mouse model of ovarian cancer, ALDH1A1 silencing using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy, significantly reducing tumor growth in mice compared with chemotherapy alone (a 74%-90% reduction; P < 0.015). These data show that the ALDH1A1 subpopulation is associated with chemoresistance and outcome in ovarian cancer patients, and targeting ALDH1A1 sensitizes resistant cells to chemotherapy. ALDH1A1-positive cells have enhanced, but not absolute, tumorigenicity but do have differentiation capacity lacking in ALDH1A1-negative cells. This enzyme may be important for identification and targeting of chemoresistant cell populations in ovarian cancer.
Purpose: Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial
cancer is not fully known. Therefore, we examined the clinical ...and therapeutic significance of VEGF in endometrial carcinoma
using patient samples and an endometrioid orthotopic mouse model.
Experimental Design: Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using
immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated
with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly
into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were
analyzed for markers of angiogenesis and proliferation.
Results: Of 111 endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation between VEGF
expression and MVD ( P < 0.001). On multivariate analysis, stage ( P = 0.04), grade ( P = 0.003), VEGF levels ( P = 0.03), and MVD ( P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab
alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97%
inhibition over controls; P < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls;
P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001).
Conclusions: Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients.
Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with
docetaxel is highly efficacious and should be considered for future clinical trials.
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