Dual and opposing roles of the androgen receptor in VETC-dependent and invasion-dependent metastasis of hepatocellular carcinoma

Zhou, Honghang; Liu, Chu-Xing; Pan, Weidong; Shang, Li-Ru; Zheng, Jialin; Huang, Bi-Yu; Chen, Jieying; Zheng, Limin; Fang, Jian‐Hong; Zhuang, Shi‐Mei

doi:10.1016/j.jhep.2021.04.053

Cited by 31 publications

(19 citation statements)

References 28 publications

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“…This result supports that VETC facilitates haematogenous metastasis to the lung, by allowing these vascular endothelium‐coated HCC clusters to enter the circulation 12 . Recently, androgen receptor (AR) was reported to have a dualistic role; in AR‐low condition, angiopoietin‐2 (Ang2) increased vascular remodelling and promoted VETC‐mediated metastasis, whereas in AR‐high condition, Rac1 promoted lamellipodia formation and invasion‐mediated metastasis 43 . MTM subtype was also more frequently observed in lung metastases than other organ metastases.…”

Section: Discussionsupporting

confidence: 66%

“…12 Recently, androgen receptor (AR) was reported to have a dualistic role; in AR-low condition, angiopoietin-2 (Ang2) increased vascular remodelling and promoted VETC-mediated metastasis, whereas in AR-high condition, Rac1 promoted lamellipodia formation and invasion-mediated metastasis. 43 MTM subtype was also more frequently observed in lung metastases than other organ metastases. We have previously reported that VETC-HCCs were significantly enriched in MTM-HCCs, although VETC-HCC can be found with both macrotrabecular and microtrabecular patterns.…”

Section: Discussionmentioning

confidence: 93%

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Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects

Woo

Rhee

Yoo

et al. 2021

Liver International

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Background & Aims: Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. Methods:We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)related markers were performed.Results: Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC-HCC and macrotrabecular-massive (MTM)-HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT-high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD-L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD-L1 expression and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (P < .05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n = 32).Conclusions: Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT-high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 93%

Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects

Woo

Rhee

Yoo

et al. 2021

Liver International

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“…The overexpression of Ang-2 can promote VETC-mediated metastasis. 40 , 41 Research has shown that compared with its expression in non-MTM-HCC, VETC is more easily expressed in MTM-HCC (P=0.006) and is prone to recurrence at an early stage, with lower disease free survival and overall survival. 42 …”

Section: Molecular and Histological Features Related To Mtm-hccmentioning

confidence: 99%

Macrotrabecular-Massive Hepatocellular Carcinoma: What Should We Know?

Li¹,

Yao²,

Liu³

et al. 2022

JHC

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Hepatocellular carcinoma is one of the most common malignancies globally. Recently, a newly identified histological subtype, designated as “macrotrabecular-massive hepatocellular carcinoma” (MTM-HCC), has been associated with an aggressive phenotype and has received extensive attention. MTM-HCC was a strong independent prognostic predictor of early and overall recurrence because it is closely related to tumor molecular subclass, gene mutation, carcinogenesis pathways, and immunohistochemical markers. In addition, preoperative imaging examination can potentially provide an essential clue for diagnosing MTM-HCC, intratumor necrosis or ischemia is an independent predictor for MTM-HCC on Gd-EOB-DTPA enhanced MRI or CT. Early diagnosis and appropriate treatment of MTM-HCC could prove beneficial for preventing early recurrence and could improve outcomes.

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“…Eleven of them are also upregulated in metastatic tumours. The androgen receptor (AR) activation regulates several pathways leading to different processes like proliferation, migration and invasiveness [42]. AR correlates with a good prognosis in ER-positive breast cancer patients and controls progression and drug resistance in ER-negative [43].…”

Section: Metastasis Influence Genes Correlate With Distant Metastasis...mentioning

confidence: 99%

Role of germline variants in the metastasis of breast carcinomas

et al. 2022

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Most cancer-related deaths in breast cancer patients are associated with metastasis, a multistep, intricate process that requires the cooperation of tumour cells, tumour microenvironment and metastasis target tissues. It is accepted that metastasis does not depend on the tumour characteristics but the host's genetic makeup. However, there has been limited success in determining the germline genetic variants that influence metastasis development, mainly because of the limitations of traditional genome-wide association studies to detect the relevant genetic polymorphisms underlying complex phenotypes. In this work, we leveraged the extreme discordant phenotypes approach and the epistasis networks to analyse the genotypes of 97 breast cancer patients. We found that the host's genetic makeup facilitates metastases by the dysregulation of gene expression that can promote the dispersion of metastatic seeds and help establish the metastatic niche-providing a congenial soil for the metastatic seeds.

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Dual and opposing roles of the androgen receptor in VETC-dependent and invasion-dependent metastasis of hepatocellular carcinoma

Cited by 31 publications

References 28 publications

Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects

Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects

Macrotrabecular-Massive Hepatocellular Carcinoma: What Should We Know?

Role of germline variants in the metastasis of breast carcinomas

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