Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue

Abstract

The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.

Insulin-like growth factor-1 signaling in the tumor microenvironment: Carcinogenesis, cancer drug resistance, and therapeutic potential

“…Early studies strongly support that periprostatic adipose tissue, particularly under metabolic syndrome-associated inflammation, is a key player in the development of prostate cancer, through the IGF-1 axis, adipokines, and sex hormones ( 28 , 29 ). Overall, there is a crosstalk between cancer cells and the periprostatic adipose tissue, locally-produced adipokines support the development of the tumor microenvironment, and fatty acid-binding protein 4 (FABP4) released by adipocytes would constitute an energy source for tumor cell invasion ( 28 , 30 ).…”

The Juggernaut of Adaptive Metabolism in Cancers: Implications and Therapeutic Targets

“…AlZaim et al focused on the relationship between metabolic disorders and the incidence, risk, increased aggressiveness, and enhanced progression and metastasis of prostate cancer [ 13 ]. The review focused on the unique molecular mechanisms involved in the thrombo-inflammatory processes implicated in adipose tissue dysfunction and its relation to prostate cancer [ 13 ].…”

“…AlZaim et al focused on the relationship between metabolic disorders and the incidence, risk, increased aggressiveness, and enhanced progression and metastasis of prostate cancer [ 13 ]. The review focused on the unique molecular mechanisms involved in the thrombo-inflammatory processes implicated in adipose tissue dysfunction and its relation to prostate cancer [ 13 ]. An in-depth review of the role of the periprostatic adipose tissue (PPAT) and pleotropic implications of several coagulation cascade factors, including the tissue factor, thrombin, and active factor X, and their role in driving the development and progression of prostate cancer was provided [ 13 ].…”

“…The review focused on the unique molecular mechanisms involved in the thrombo-inflammatory processes implicated in adipose tissue dysfunction and its relation to prostate cancer [ 13 ]. An in-depth review of the role of the periprostatic adipose tissue (PPAT) and pleotropic implications of several coagulation cascade factors, including the tissue factor, thrombin, and active factor X, and their role in driving the development and progression of prostate cancer was provided [ 13 ]. The authors also proposed several novel PPAT-related therapeutic targets and possible therapeutic interventions that could effectively reverse the adverse effects of the thrombo-inflammatory processes on prostate cells and reduce the risk and progression of prostate cancer [ 13 ].…”

“…An in-depth review of the role of the periprostatic adipose tissue (PPAT) and pleotropic implications of several coagulation cascade factors, including the tissue factor, thrombin, and active factor X, and their role in driving the development and progression of prostate cancer was provided [ 13 ]. The authors also proposed several novel PPAT-related therapeutic targets and possible therapeutic interventions that could effectively reverse the adverse effects of the thrombo-inflammatory processes on prostate cells and reduce the risk and progression of prostate cancer [ 13 ]. However, in-depth analyses are required to specify the precise pharmacology and cell signaling pathways of perspective drugs such as direct oral anticoagulants or protease-activated receptor ligands.…”