Estrogens and the Schrödinger’s Cat in the Ovarian Tumor Microenvironment

Abstract

Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor microenvironment may display a tumor‑protective and ‑destructive role. Systemic and locally synthesized estrogens contribute to the formation of a pro-tumoral microenvironment that enables the sustained tumor growth, invasion and metastasis. Here we focus on the estrogen biosynthetic and metabolic pathways in ovarian cancer and elaborate their actions on phenotypically plastic, estrogen-responsive, aging immune cells of the tumor microenvironment, altogether highlighting the multicomponent-connectedness and complexity of cancer, and contributing to a broader understanding of the ovarian cancer biology.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

“…Contrary to our expectations, the patient who had an aberrantly high ER STP activity (without concurrent aberrant STPs) did not benefit from AHT. This suggests other underlying AHT‐resistance mechanisms in which possibly both intracellular factors, such as crosstalk, and extracellular factors, such as local estrogen production causing an immune response, play a key role in the development of resistance 29 …”

“…However, in LGOC, the ER STP might not be as active as is believed because only one patient exhibited aberrantly high ER STP activity in recurrent LGOC 8,9,30 . High STP activity can be possibly explained by ER signaling mechanisms, such as autocrine production of estradiol (direct‐genomic signaling) 29 . Also, local estrogens call for an immune response, changing the function of subpopulations of cells from tumor‐suppressing to tumor‐promoting.…”

“…This suggests other underlying AHTresistance mechanisms in which possibly both intracellular factors, such as crosstalk, and extracellular factors, such as local estrogen production causing an immune response, play a key role in the development of resistance. 29 Based on high ER protein expression, previous studies suggested that the ER STP is generally highly active in (LG)OC. However, in…”

“…8,9,30 High STP activity can be possibly explained by ER signaling mechanisms, such as autocrine production of estradiol (direct-genomic signaling). 29 Also, local estrogens call for an immune response, changing the function of subpopulations of cells from tumor-suppressing to tumor-promoting. The change to a tumorpromoting environment possibly results from the STP activity of immune cells themselves, particularly the PI3K STP, which plays an important positive and negative role in cellular response.…”

What’s beyond BRCA Mutational Status in High Grade Serous Ovarian Cancer? The Impact of Hormone Receptor Expression in a Large BRCA-Profiled Ovarian Cancer Patient Series: A Retrospective Cohort Study

“…Therefore, we would expect that the direct role played by BRCA1 in the control of ERα-mediated transcription reduces oestrogen’s effects on proliferation, angiogenesis, and TME-mediated tumour growth. This might be particularly relevant when considering that: (a) high E2 levels are often observed in OC patients/tissues (reviewed by [ 29 , 30 ]), and (b) carriers of BRCA1/2 mutations have increased oestrogen levels [ 16 ].…”