Androgen receptor, neovascularization and liver cancer metastasis

Abstract

The mechanisms underlying the recurrence and metastasis of hepatocellular carcinoma (HCC) are poorly understood. In 2015, Zhuang and her colleagues identified a unique histopathological structure in HCC tissues, which they dubbed VETC, standing for vessels that encapsulate tumor clusters. 1 In the VETC structure, sinusoid-like vessels form a cobweb-like network that encapsulates individual tumor cell clusters. These endotheliumwrapped tumor cell clusters were released into the blood stream and formed metastatic tumors in a manner independent of epithelial-mesenchymal transition (EMT), another wellknown tumor metastatic process. 2 Mechanistically, the authors found that angiopoietin-2 (Angpt2) secreted by tumor cells played a critical role in the induction of VETC formation and intrahepatic tumor metastasis and recurrence.In this issue, Zhuang's group report a very interesting functional relationship between androgen receptor (AR) and VETC formation in intrahepatic and extrahepatic metastasis of liver cancer. 3 AR is a member of the nuclear hormone receptor superfamily whose elevated expression has been implicated in HCC development. 4 Paradoxically, genetic deletion of AR in hepatocytes delayed mouse HCC initiation driven by diethylnitrosamine, but exacerbated later tumor growth and metastasis to the lung, demonstrating complex mechanisms of AR activity in HCC. 5 Consistently, an AR antagonist did not show significant therapeutic benefit for patients with HCC in clinical trials. 6 To further elucidate the roles of AR in HCC, the investigators examined nuclear AR contents in 241 HCC samples collected in the Cancer Center of Sun Yat-sen University. Interestingly, lower levels of nuclear AR and VETC formation significantly correlated with higher risk of HCC recurrence and poor survival. This data was validated in another cohort of patients with HCC using the TCGA dataset. Reduced AR expression was also associated with HCC cases with portal vein tumor thrombus. To explore a causative role of AR in VETC-dependent metastasis, the authors expressed mouse AR in Hepa1-6 hepatoma cells, which form VETC+ tumors. Overexpression of AR suppressed VETC formation in xenografts and also intrahepatic metastasis, while increasing the numbers and sizes of metastasized foci in the lung. Next, the authors interrogated the molecular mechanisms underlying the effects of AR.Their previous experiments showed that high expression of Angpt2 was required for VETC formation. 1 In the present study, the

The Interplay between Finasteride-Induced Androgen Imbalance, Endoplasmic Reticulum Stress, Oxidative Stress, and Liver Disorders in Paternal and Filial Generation

“…In the patient samples, a lower AR correlated with higher metastatic risk and poorer survival in liver cancers. The authors also paid attention to the specific type of peritumoral vascularization and the expression of Rac (plasma membrane-associated small GTPase) and angiopoietin [ 92 ].…”

Oridonin suppresses gastric cancer SGC‐7901 cell proliferation by targeting the TNF‐alpha/androgen receptor/TGF‐beta signalling pathway axis

“…AR is the androgen receptor, and AR signalling pathway is related to many hormone‐dependent diseases such as prostate cancer, 49 breast cancer 50 , 51 , 52 and ovarian cancer, 53 as well as malignant tumours, for example gastric cancer, 54 , 55 lung cancer, 56 , 57 bladder cancer, 58 , 59 pancreatic cancer, 60 , 61 liver cancer 62 and kidney cancer. 63 The distribution of AR in cells is closely related to the survival of tumours.…”

“…pancreatic cancer, 60,61 liver cancer 62 and kidney cancer. 63 The distribution of AR in cells is closely related to the survival of tumours.…”

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

“…Since the incidence of obesity-related HCC is much higher in men than in women, androgen receptors may produce ontogenetic efficacy through alternative mechanisms, such as interaction with signal transducer and activator of transcription 3 (STAT3) [ 129 ]. AR plays a role in developing of neovascularization and liver cancer metastasis, which may participate in the progression from NASH to HCC [ 130 ].…”