Treatment for Advanced and Recurrent Endometrial Carcinoma: Combined Modalities

Rauh‐Hain, J. Alejandro; Carmen, Marcela G. del

doi:10.1634/theoncologist.2010-0091

Cited by 54 publications

(31 citation statements)

References 72 publications

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“…However, patients with advanced stage disease (FIGO stage III and IV) have a 5-year survival of 21–56%. Patients with advanced stage III or IV disease are unlikely to be cured by surgery, conventional chemotherapy, radiation or a combination of these modalities [4]. Given the rising incidence of this disease and the paucity of effective treatments for advanced and recurrent endometrial cancer, understanding the energy metabolism in endometrial cancer cells will help develop new approaches for the effective management of this obesity-driven malignancy.…”

Section: Introductionmentioning

confidence: 99%

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Han

Zhang

Guo

et al. 2015

Gynecologic Oncology

146

109

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Objectives Obesity and diabetes are well-known risk factors for the development of endometrial cancer. A high rate of aerobic glycolysis represents a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. This study aimed to investigate the effect of various concentrations of glucose on cell proliferation in endometrial cancer. Methods ECC-1 and Ishikawa cells were treated with low glucose (1mM), normal glucose (5mM) and high glucose (25mM), and cytotoxicity, apoptosis, cell cycle, adhesion/invasion, and changes of AMPK/mTOR/S6 and MAPK pathways were evaluated. Results Our results revealed that high glucose increased cell growth and clonogenicity in two endometrial cancer cell lines in a dose dependent manner. Low glucose induced the activity of cleaved caspase 3 and caused cell cycle G1 arrest. High glucose increased the ability of adhesion and invasion by decreasing E-Cadherin and increasing Snail expression. In addition, high glucose increased glucose uptake and glycolytic activity through modulating the AMPK/mTOR/S6 and MAPK pathways. Conclusions Our findings suggest that glucose stimulated cell proliferation through multiple complex signaling pathways. Targeting glucose metabolism may be a promising therapeutic strategy in the treatment of endometrial cancer.

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Section: Introductionmentioning

confidence: 99%

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Han

Zhang

Guo

et al. 2015

Gynecologic Oncology

146

109

View full text Add to dashboard Cite

show abstract

“…Several treatment options, such as hysterectomy, hormonal therapy, and combinations of radiation and chemotherapy are effective for early stage EC; however, only limited options remain if the tumors metastasize (Rauh-Hain & del Carmen 2010).…”

Section: Introductionmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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“…While this approach may be curative, it causes loss of fertility and can induce life-long side effects. Patients with metastatic disease often succumb to the cancer despite aggressive treatments (14). Discovery of reliable biomarkers that predict responsiveness to progesterone therapy and molecular mechanisms that dictate hormone sensitivity or resistance could broaden the application of hormonal therapy to endometrial cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Progesterone Receptor Signaling in the Microenvironment of Endometrial Cancer Influences Its Response to Hormonal Therapy

et al. 2013

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Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited due to the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we demonstrate that signaling through stromal PR is necessary and sufficient for progesterone anti-tumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results demonstrate that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic de-repression of stromal PR could be a potential therapeutic target for sensitizing hormone refractory endometrial tumors to progesterone therapy. Based on these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy.

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Treatment for Advanced and Recurrent Endometrial Carcinoma: Combined Modalities

Cited by 54 publications

References 72 publications

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Glucose promotes cell proliferation, glucose uptake and invasion in endometrial cancer cells via AMPK/mTOR/S6 and MAPK signaling

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Progesterone Receptor Signaling in the Microenvironment of Endometrial Cancer Influences Its Response to Hormonal Therapy

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