scholarly journals Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1145
Author(s):  
Erin G. Shackleton ◽  
Haleema Yoosuf Ali ◽  
Masood Khan ◽  
Graham A. Pockley ◽  
Stephanie E. McArdle
Keyword(s):  
Prostate Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Therapy Resistance ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Interventions ◽  
Th2 Cells ◽  
Low Grade ◽  
Castration Resistance

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients.

scholarly journals The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

2021 ◽  
Author(s):  
Ielizaveta Gorodetska ◽  
Anna Offermann ◽  
Jakob Pueschel ◽  
Vasyl Lukiyanchuk ◽  
Diana Gaete ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Therapy Resistance ◽  
Radiation Sensitivity ◽  
Strand Break ◽  
Mesenchymal Transition

Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

Expression of transforming growth factor-beta 1 in prostate cancer.

Endocrinology ◽  
1994 ◽  
Vol 135 (5) ◽  
pp. 2240-2247 ◽  
Author(s):  
M S Steiner ◽  
Z Z Zhou ◽  
D C Tonb ◽  
E R Barrack
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Factor Beta

scholarly journals Transforming of the Tumor Microenvironment: Implications for TGF-βInhibition in the Context of Immune-Checkpoint Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stefanie Löffek
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor Beta ◽  
Immune Checkpoint ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Therapy Response ◽  
Initial Therapy ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Oncogenic Signaling

Significant breakthroughs have been achieved in the fields of oncogenic signaling inhibition and particularly immune-checkpoint blockade has triggered substantial enthusiasm during the last decade. Antibody-mediated blockade of negative immune-checkpoint molecules (e.g., PD-1/PD-L1, CTLA-4) has been shown to achieve profound responses in several of solid cancers. Unfortunately, these responses only occur in a subset of patients or, after initial therapy response, these tumors eventually relapse. Thus, elucidating the determinants of intrinsic or therapy-induced resistance is the key to improve outcomes and developing new treatment strategies. Several cytokines and growth factors are involved in the tight regulation of either antitumor immunity or immunosuppressive tumor-promoting inflammation within the tumor microenvironment (TME), of which transforming growth factor beta (TGF-β) is of particular importance. This review will therefore summarize the recent progress that has been made in the understanding of how TGF-βblockade may have the capacity to enhance efficacy of immune-checkpoint therapy which presents a rational strategy to sustain the antitumor inflammatory response to improve response rates in tumor patients. Finally, I will conclude with a comprehensive summary of clinical trials in which TGF-βblockade revealed therapeutic benefit for patients by counteracting tumor relapses.

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