The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Bonollo, Francesco; Thalmann, George N.; Julio, Marianna Kruithof-de; Karkampouna, Sofia

doi:10.3390/cancers12071887

Cited by 97 publications

(103 citation statements)

References 171 publications

(311 reference statements)

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“…CAFs are one of the most abundant and critical cellular components involved in promoting tumor development and progression [ 57 ]. During early tumor initiation, CAFs are activated by adjacent tumor cells via paracrine signaling to cultivate a desmoplastic, pro-tumorigenic microenvironment [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

Teng

Pereira

Keerthikumar

et al. 2021

Cancers

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Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

Teng

Pereira

Keerthikumar

et al. 2021

Cancers

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“…Furthermore, another factor involved in the importance of the TME in tumor resistance to ICIs is the role of cancer-associated fibroblasts (CAFs), the predominant cell type in the TME. CAFs promote PC carcinogenesis, metastatic progression and therapy resistance by promoting a reactive stroma [ 101 ]. It is well described that PC cells establish a crosstalk with CAFs and inflammatory cells to coordinate immune cell recruitment and activation through several signalling factors, including cytokines, chemokines, and growth factors [ 101 , 102 ].…”

Section: Mechanisms Of Resistance and Potential Predictive Biomarkers Of Ici Responsementioning

confidence: 99%

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Porras

Pardo

Notario

et al. 2021

IJMS

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Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.

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“…CAFs are the most prevalent component of the TME stroma and are responsible for the generation of a ‘reactive stroma’ in response to the presence of PCa cells. This is achieved through accelerated ECM turn-over and remodeling, which permits the release of previously tissue-associated molecules known for promoting growth and survival [ 83 ]. This wound-healing response mechanism is continuously maintained by PCa cells, which secrete CAF-promoting TGFβ.…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 99%

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

Shackleton

Ali

Khan

et al. 2021

Cancers

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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.

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The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cited by 97 publications

References 171 publications

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

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