The Role of the Estrogen Pathway in the Tumor Microenvironment – PMC

LRH-1) was upregulated in CAFs compared to normal fibroblastsnHighlight:Aromatase is found to be co-expressed in breast cancers with LRH-1, suggesting a paracrine mechanism of E2 synthesis and ER-mediated oncogenesis in the breast cancer TMEnHighlight:ERα is also expressed in prostate CAFsnHighlight:TAMs can promote tumor cell proliferation, an inflammatory microenvironment, and metastasisnHighlight:polarized M1 macrophages produce proinflammatory cytokines including IFNγ, interleukin 12 (IL-12), and TNFα, that contribute to tumor rejection and antigen presentationnHighlight:macrophages exhibiting an M2 phenotype produce type-2 cytokines including interleukins 4,5,6, and 10 [], all of which are identified promoters of tumor progression through enhanced tumor cell growth and immune evasionnHighlight:TAMs observed in malignant tumors display an M2 phenotypenHighlight:TAM infiltration is observed in a wide-range of cancer types and correlates with poor prognosisnHighlight:premenopausal patients show elevated TAM infiltration compared to postmenopausal women, with highest overall TAM density observed in ERα-positive tumorsnHighlight:aromatase expression in TAMs, enabling local E2 production within the TME and enhanced ER-positive breast tumor cell proliferationnHighlight:Aromatase is also expressed in TAMs from NSCLCnHighlight:E2 can induce M2 polarization and tumor infiltrationnSticky notes:BOOM!nHighlight:E2 increased tumoral M2 TAM infiltration, while untreated controls alternatively exhibited M1 TAM infiltrationnHighlight:E2 enhanced M2 macrophage secretion of vascular endothelial growth factor (VEGF), an identified mediator of M2 macrophage recruitmentnHighlight:E2 has been shown to also upregulate VEGF expression and pulmonary macrophage contentnHighlight:E2 not only enhanced the growth of ER-negative xenografts, but also increased M2 TAM infiltration compared to untreated ovariectomizednSticky notes:Points to E2 not just in ER of the cancer cell, but of the TME and TAMs, particularly the M2 varietynHighlight:endometrial M2 TAMs mediate ER activation through epigenetic upregulation of ERα by secreted interleukin-17A (IL-17A), increasing E2-driven malignant endometrial cell proliferationnSticky notes:Vicious cyclenHighlight:positive feedback mechanism between the estrogen pathway and M2 TAM infiltration in certain cancersnHighlight:resveratrol treatment significantly suppressed tumor growth by inhibiting M2 polarization of TAMs and decreasing activation of signal transducer and activator of transcription 3 (STAT3) signalingnSticky notes:Resveratrol inhibits M2 Polarization of TAMs; decreased STAT3 signaling as wellnHighlight:MDSCs are another myeloid cell present in the TME known to disrupt immune surveillance and promote tumor developmentnHighlight:E2-treated mice also exhibited significantly fewer helper and cytotoxic T cells, but also exhibited significantly elevated recruitment of MDSCs in both the spleen and tumor bedsnHighlight:ER-dependence of MDSC expansionnHighlight:E2 treatment increased activation of STAT3 signaling, a regulator of myeloid differentiation and developmentnHighlight:CD4+ T cell polarization has been identified as a mediator of tumor immune surveillance. T helper 1 (Th1) T cell responses are associated with tumor suppression and upregulation of IFNγ and IL-12, while T helper 2 (Th2) responses are reliant of IL-4 production and exhibit protumor activitynHighlight:elevated E2 induces increased Th2 responses and upregulate IL-4 productionnHighlight:inverse correlation between ER activity and immune infiltration of each of these cells in breast cancer tissuesnHighlight:increased TIL, specifically CD8+ T cells, in ER-negative tumors significantly correlates with improved OSnHighlight:AI letrozole increased the infiltration of B cell and T helper lymphocyte subsets at early and late time points following treatment initiationnSticky notes:Not just about Aromatase inhibition, but also effect on the TIMEnHighlight:E2 enhances immunosuppression through inhibition of NK and CTL-mediated tumor cell eliminationnHighlight:FoxP3 expressing Tregs are integral in coordinating suppression of anti-tumor immune responses, secreting immunosuppressive cytokines and inhibiting responder T cell expansionnHighlight:FoxP3+ Treg infiltration significantly correlated with poorer OS in ER-positive breast cancer patients, but improved survival rates in ER-negative patientsnHighlight:evaluation of ERα-positive breast tumors from patients treated with letrozole showed a significant reduction of FoxP3+ Tregs post-treatmentnSticky notes:Again, AI not just about aromatase inhibition, but also TIME, here specifically the Treg infiltration/activity in the TME.nHighlight:Tregs isolated from mice treated with E2 displayed enhanced suppression and increased intracellular expression of the immune checkpoint protein programmed death-1 (PD-1), while ERα and ERβ knockout reduced Treg suppression and PD-1 expressionnHighlight:E2 treatment also stimulates in vitro expression of the PD-1 ligand (PD-L1) on ERα-positive endometrial and breast cancer cells through activation of PI3K signalingnHighlight:Interactions between PD-L1 expressing tumor cells and PD-1 positive T cells induces cytotoxic T cell exhaustion, resulting in tumor immune evasionnSticky notes:Key; and estrogen increases thisnHighlight:Evidence that E2 upregulates both PD-L1 and PD-1, suggests E2 signaling may critically influence the PD-1/PD-L1 pathwaynHighlight:TME releases cytokines that activate protumoral pathways mediating proliferation, immune evasion, and metastasisnHighlight:IL-6, a proinflammatory cytokine, has been shown to enhance ERα-positive breast cancer cell growth and invasionnHighlight:Local TAFs in breast cancers act as a paracrine source of the elevated IL-6, driving STAT3 activation and ERα-positive tumor cell proliferation both in vitro and in vivonHighlight:TNFα has also been shown to upregulate aromatase expression in cultured human adipose stromal cellsnHighlight:Transcriptional linear correlations between aromatase and the cytokines TNFα and IL-6 have been reported in patient breast cancer tissue, but not in adjacent non-cancerous tissuenHighlight:similar correlation has also been seen between aromatase and the eicosanoid cyclooxygenase-2 (COX-2)nSticky notes:LinearnHighlight:PGE2 promotes upregulated transcription of aromatase through elevated cyclic adenosine monophosphate (cAMP) in breast tumorsnHighlight:activation of NF-κB is observed in several cancers, and is associated with the cytokines IL-6 and TNFαnHighlight:E2 exposure in a murine model evaluating tobacco-induced lung cancer enhanced pulmonary inflammation through increased activation of NF-κB signaling and expression of VEGF and IL-17AnHighlight:targeting E2 and inflammatory pathways with combined AI and NSAID treatment maximally prevented carcinogen-induced lung tumor development in mice, significantly reducing STAT3 and MAPK signaling, circulating IL-6, and IL-17A expressionnHighlight:typical response rates to these therapies remain limited to only around 20–35% of patientsnHighlight:E2 signaling can modulate the immune TME through enhanced protumoral responsesnHighlight:anti-estrogen therapy has the potential to not only reverse an immunosuppressive TME, but also to augment response in E2-sensitive tumors.nHighlight:E2 pathway promotes a protumor TMEnHighlight:E2 may facilitate an immunosuppressive TME by shifting the balance in favor of Th2 responses, production of tumor-promoting cytokines (IL-6, IL-4, TNFα, and IL-17A), and M2 TAM infiltration compared to Th1 responses, associated Th1 cytokines (IL-12 and IFNγ), and M1 TAM infiltrationnHighlight:E2 may further promote tumor immune evasion through proliferation of Treg and MDSC populations, increased tumor cell PD-L1 expression, and inhibition of CD8+ T cell and NK cell induced apoptosisnHighlight:CAFs may additionally support a protumor environment by supplying paracrine sources of E2 and IL-6nHighlight:anti-estrogen fulvestrant as the top compound that increased tumor sensitivity to immune-mediated lysisnHighlight:Fulvestrant is an ideal candidate to combine with anti-PD-1/PD-L1 agentsnHighlight:anti-estrogen therapy to target the immunosuppressive TME, thereby increasing the efficacy and duration of response of current immunotherapiesn]]>

Picture of About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.


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