- Title
- Role of microenvironment in endometrial cancer progression, metastasis, and drug resistance
- Creator
- Sahoo, Subhransu Sekhar
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Endometrial cancer is the most frequently diagnosed cancer of the female reproductive tract. Obesity is an independent risk factor for this disease and approximately 50% of cases are associated with high body mass index (BMI). Like many cancers, the progression of high-grade or metastatic endometrial cancer is mediated through a supportive tumor microenvironment (TME). Currently, the precise role of TME towards endometrial cancer progression is unclear. To manifest the tumor-stroma interaction, we investigated both non-cellular (extracellular matrix, ECM) and cellular (adipocyte) components of the endometrial cancer microenvironment. 1) In the first part, we found that conversion of glandular epithelium of endometrial cells to non-glandular epithelium is a hallmark of cancer, and this transition is facilitated by TGF-β signaling through ECM. Mechanistically our results revealed that fibronectin of ECM facilitates activation of TGF-β pathway and promotes metastasis. Moreover, interruption of TGF-β signaling significantly suppresses endometrial cancer metastasis. 2) In the second part, we demonstrated the interaction between adipocytes and endometrial cancer cells using human biopsies and a hyperphagic obese mouse model. We found that hypertrophied adipocytes secrete VEGF, which stimulates angiogenesis in the uterus as well as endometrial cell proliferation through active mTOR signaling. Taken together these findings provide new understanding on TME during endometrial carcinogenesis and render novel ideas of co-targeting tumor cells as well as stromal signals to suppress metastatic progression. 3) Furthermore, inhibiting microenvironment-derived signals, early diagnosis of the disease is necessary to suppress the spread of cancer. Therefore, we examined differential expression of soluble and secreted proteins in healthy and cancer patients and found placental-like alkaline phosphatase (ALPPL2) as a potential secreted protein in endometrial cancer patients. Interestingly with the existing knowledge of hyperestrogenic state is a major risk factor for endometrial cancer, our results ascertained that estrogen stimulates expression of this protein. Thus, ALPPL2 can be used as a prognostic biomarker for endometrial cancer. Collectively our research provides new insights towards endometrial cancer microenvironment as well as its early diagnosis.
- Subject
- endometrial cancer; tumor microenvironment; ECM; adipocyte; prognostic biomarker; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1386299
- Identifier
- uon:32397
- Rights
- Copyright 2018 Subhransu Sekhar Sahoo
- Language
- eng
- Full Text
- Hits: 2659
- Visitors: 1446
- Downloads: 486
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 21 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 275 KB | Adobe Acrobat PDF | View Details Download |