Cancers

Research

14 pages, 757 KiB

Open AccessArticle

Circulatory Agrin Serves as a Prognostic Indicator for Hepatocellular Carcinoma

by Ankita Kapoor, Reza Bayat Mokhtari, Sahithi Savithri Sonti, Riya Patel, Anthony George, Kristopher Attwood, Renuka Iyer and Sayan Chakraborty

Cancers 2024, 16(15), 2719; https://doi.org/10.3390/cancers16152719 - 31 Jul 2024

Viewed by 967

Abstract

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is associated with high mortality rates both in the United States and globally. Despite current advances in immunotherapy regimens, there is a scarcity of biomarkers to guide therapy selection. Alpha-fetoprotein (AFP) and glypican-3 have [...] Read more.

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is associated with high mortality rates both in the United States and globally. Despite current advances in immunotherapy regimens, there is a scarcity of biomarkers to guide therapy selection. Alpha-fetoprotein (AFP) and glypican-3 have been proposed as biomarkers for HCC, but they do not provide any prognostic benefit for modeling disease progression. Agrin, a secreted proteoglycan, is frequently overexpressed in HCC and plays prominent role(s) in the liver tumor microenvironment (TME) to promote hepatocarcinogenesis. Here we employed a pilot single-center retrospective investigation to assess the prognostic value of agrin in HCC. Our evidence suggests that elevated serum agrin levels are associated with poor prognosis and performance among HCC patients. Multivariate Cox regression models indicate that secreted agrin serves as a better prognostic indicator compared to AFP that is significantly correlated with other secreted biomarkers (e.g., IL6). Cumulatively, this work demonstrates a promising clinical value of agrin in the detection and prognosis of HCC. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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21 pages, 7098 KiB

Open AccessArticle

Comprehensive Molecular Analysis Identified an SRSF Family-Based Score for Prognosis and Therapy Efficiency Prediction in Hepatocellular Carcinoma

by Jingsheng Yuan, Zijian Liu, Zhenru Wu, Jiayin Yang and Tao Lv

Cancers 2022, 14(19), 4727; https://doi.org/10.3390/cancers14194727 - 28 Sep 2022

Cited by 3 | Viewed by 2295

Abstract

The serine/arginine-rich splicing factors (SRSF)-mediated alternative splicing plays an essential role in the occurrence and progression of hepatocellular carcinoma (HCC). However, the SRSF-based signature that can predict the prognosis and therapy efficiency is yet to be investigated in HCC. Here, we comprehensively assessed [...] Read more.

The serine/arginine-rich splicing factors (SRSF)-mediated alternative splicing plays an essential role in the occurrence and progression of hepatocellular carcinoma (HCC). However, the SRSF-based signature that can predict the prognosis and therapy efficiency is yet to be investigated in HCC. Here, we comprehensively assessed the landscape and prognostic significance of the SRSF family genes in HCC. Then, we screened the SRSF family-related genes for signature construction and explored their biological characteristics. We further established an SRSF score consisting of 18 SRSF-associated genes and evaluated its correlation with prognosis and drug sensitivity in HCC. The predictive power of the SRSF score was validated in independent HCC cohorts and different HCC subgroups. Moreover, we further investigated that knockdown of SRSF11, a pivotal gene in the SRSF score, inhibited CDK1-dependent proliferation and enhanced the drug sensitivity of HCC cells. Overall, our study identified a novel SRSF family-based predictive model, and we demonstrated that SRSF11 is a promising therapeutic target for HCC, which enhances our understanding of the SRSF family genes and provides valuable insights into the clinical treatment and molecular mechanisms of HCC. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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Review

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12 pages, 259 KiB

Open AccessReview

Impact of Hypoxia on Radiation-Based Therapies for Liver Cancer

by Alexander Villalobos, Jean Lee, Sarah A. Westergaard and Nima Kokabi

Cancers 2024, 16(5), 876; https://doi.org/10.3390/cancers16050876 - 22 Feb 2024

Viewed by 1455

Abstract

Background: Hypoxia, a state of low oxygen level within a tissue, is often present in primary and secondary liver tumors. At the molecular level, the tumor cells’ response to hypoxic stress induces proteomic and genomic changes which are largely regulated by proteins called [...] Read more.

Background: Hypoxia, a state of low oxygen level within a tissue, is often present in primary and secondary liver tumors. At the molecular level, the tumor cells’ response to hypoxic stress induces proteomic and genomic changes which are largely regulated by proteins called hypoxia-induced factors (HIF). These proteins have been found to drive tumor progression and cause resistance to drug- and radiation-based therapies, ultimately contributing to a tumor’s poor prognosis. Several imaging modalities have been developed to visualize tissue hypoxia, providing insight into a tumor’s microbiology. Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, and Google Scholar for all reports related to hypoxia on liver tumors. All relevant studies were summarized. Results: This review will focus on the impact of hypoxia on liver tumors and review PET-, MRI-, and SPECT-based imaging modalities that have been developed to predict and assess a tumor’s response to radiation therapy, with a focus on liver cancers. Conclusion: While there are numerous studies that have evaluated the impact of hypoxia on tumor outcomes, there remains a relative paucity of data evaluating and quantifying hypoxia within the liver. Novel and developing non-invasive imaging techniques able to provide functional and physiological information on tumor hypoxia within the liver may be able to assist in the treatment planning of primary and metastatic liver lesions. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

21 pages, 645 KiB

Open AccessReview

Functional Imaging of Hypoxia: PET and MRI

by Ryan C. Perez, DaeHee Kim, Aaron W. P. Maxwell and Juan C. Camacho

Cancers 2023, 15(13), 3336; https://doi.org/10.3390/cancers15133336 - 25 Jun 2023

Cited by 4 | Viewed by 2101

Abstract

Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of [...] Read more.

Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of hypoxia inducible factor (HIF), significant progress in understanding the regulation of hypoxia-induced genes has been made. These advances have provided the ability to therapeutically target HIF and tumor-associated hypoxia. Therefore, by utilizing the molecular basis of hypoxia, hypoxia-based theranostic strategies are in the process of being developed which will further personalize care for cancer patients. The aim of this review is to provide an overview of the significance of tumor hypoxia and its relevance in cancer management as well as to lay out the role of imaging in detecting hypoxia within the context of cancer. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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17 pages, 594 KiB

Open AccessReview

The Role of Artificial Intelligence in the Detection and Implementation of Biomarkers for Hepatocellular Carcinoma: Outlook and Opportunities

by Arian Mansur, Andrea Vrionis, Jonathan P. Charles, Kayesha Hancel, John C. Panagides, Farzad Moloudi, Shams Iqbal and Dania Daye

Cancers 2023, 15(11), 2928; https://doi.org/10.3390/cancers15112928 - 26 May 2023

Cited by 14 | Viewed by 3419

Abstract

Liver cancer is a leading cause of cancer-related death worldwide, and its early detection and treatment are crucial for improving morbidity and mortality. Biomarkers have the potential to facilitate the early diagnosis and management of liver cancer, but identifying and implementing effective biomarkers [...] Read more.

Liver cancer is a leading cause of cancer-related death worldwide, and its early detection and treatment are crucial for improving morbidity and mortality. Biomarkers have the potential to facilitate the early diagnosis and management of liver cancer, but identifying and implementing effective biomarkers remains a major challenge. In recent years, artificial intelligence has emerged as a promising tool in the cancer sphere, and recent literature suggests that it is very promising in facilitating biomarker use in liver cancer. This review provides an overview of the status of AI-based biomarker research in liver cancer, with a focus on the detection and implementation of biomarkers for risk prediction, diagnosis, staging, prognostication, prediction of treatment response, and recurrence of liver cancers. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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20 pages, 725 KiB

Open AccessReview

A Paradigm Shift in Primary Liver Cancer Therapy Utilizing Genomics, Molecular Biomarkers, and Artificial Intelligence

by James Moroney, Juan Trivella, Ben George and Sarah B. White

Cancers 2023, 15(10), 2791; https://doi.org/10.3390/cancers15102791 - 17 May 2023

Cited by 1 | Viewed by 2278

Abstract

Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest [...] Read more.

Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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13 pages, 1795 KiB

Open AccessReview

Targeting Hypoxia-Inducible Factor-1α for the Management of Hepatocellular Carcinoma

by Kenneth N. Huynh, Sriram Rao, Bradley Roth, Theodore Bryan, Dayantha M. Fernando, Farshid Dayyani, David Imagawa and Nadine Abi-Jaoudeh

Cancers 2023, 15(10), 2738; https://doi.org/10.3390/cancers15102738 - 12 May 2023

Cited by 11 | Viewed by 2510

Abstract

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as [...] Read more.

Hypoxia-inducible factor 1 alpha (HIF-1α) is a transcription factor that regulates the cellular response to hypoxia and is upregulated in all types of solid tumor, leading to tumor angiogenesis, growth, and resistance to therapy. Hepatocellular carcinoma (HCC) is a highly vascular tumor, as well as a hypoxic tumor, due to the liver being a relatively hypoxic environment compared to other organs. Trans-arterial chemoembolization (TACE) and trans-arterial embolization (TAE) are locoregional therapies that are part of the treatment guidelines for HCC but can also exacerbate hypoxia in tumors, as seen with HIF-1α upregulation post-hepatic embolization. Hypoxia-activated prodrugs (HAPs) are a novel class of anticancer agent that are selectively activated under hypoxic conditions, potentially allowing for the targeted treatment of hypoxic HCC. Early studies targeting hypoxia show promising results; however, further research is needed to understand the effects of HAPs in combination with embolization in the treatment of HCC. This review aims to summarize current knowledge on the role of hypoxia and HIF-1α in HCC, as well as the potential of HAPs and liver-directed embolization. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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37 pages, 1312 KiB

Open AccessReview

Potential Immunotherapy Targets for Liver-Directed Therapies, and the Current Scope of Immunotherapeutics for Liver-Related Malignancies

by Jonathan Charles, Andrea Vrionis, Arian Mansur, Trevor Mathias, Jamil Shaikh, Aaron Ciner, Yixing Jiang and Nariman Nezami

Cancers 2023, 15(9), 2624; https://doi.org/10.3390/cancers15092624 - 5 May 2023

Cited by 2 | Viewed by 2868

Abstract

Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or [...] Read more.

Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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20 pages, 856 KiB

Open AccessReview

Neuroendocrine Tumors: Genomics and Molecular Biomarkers with a Focus on Metastatic Disease

by Erica S. Alexander and Etay Ziv

Cancers 2023, 15(8), 2249; https://doi.org/10.3390/cancers15082249 - 12 Apr 2023

Cited by 2 | Viewed by 3484

Abstract

Neuroendocrine tumors (NETs) are considered rare tumors that originate from specialized endocrine cells. Patients often present with metastatic disease at the time of diagnosis, which negatively impacts their quality of life and overall survival. An understanding of the genetic mutations that drive these [...] Read more.

Neuroendocrine tumors (NETs) are considered rare tumors that originate from specialized endocrine cells. Patients often present with metastatic disease at the time of diagnosis, which negatively impacts their quality of life and overall survival. An understanding of the genetic mutations that drive these tumors and the biomarkers used to detect new NET cases is important to identify patients at an earlier disease stage. Elevations in CgA, synaptophysin, and 5-HIAA are most commonly used to identify NETs and assess prognosis; however, new advances in whole genome sequencing and multigenomic blood assays have allowed for a greater understanding of the drivers of NETs and more sensitive and specific tests to diagnose tumors and assess disease response. Treating NET liver metastases is important in managing hormonal or carcinoid symptoms and is imperative to improve patient survival. Treatment for liver-dominant disease is varied; delineating biomarkers that may predict response will allow for better patient stratification. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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19 pages, 395 KiB

Open AccessReview

Colorectal Cancer Liver Metastases: Genomics and Biomarkers with Focus on Local Therapies

by Yuliya Kitsel, Timothy Cooke, Vlasios Sotirchos and Constantinos T. Sofocleous

Cancers 2023, 15(6), 1679; https://doi.org/10.3390/cancers15061679 - 9 Mar 2023

Cited by 9 | Viewed by 4907

Abstract

Molecular cancer biomarkers help personalize treatment, predict oncologic outcomes, and identify patients who can benefit from specific targeted therapies. Colorectal cancer (CRC) is the third-most common cancer, with the liver being the most frequent visceral metastatic site. KRAS, NRAS, BRAF V600E Mutations, DNA [...] Read more.

Molecular cancer biomarkers help personalize treatment, predict oncologic outcomes, and identify patients who can benefit from specific targeted therapies. Colorectal cancer (CRC) is the third-most common cancer, with the liver being the most frequent visceral metastatic site. KRAS, NRAS, BRAF V600E Mutations, DNA Mismatch Repair Deficiency/Microsatellite Instability Status, HER2 Amplification, and NTRK Fusions are NCCN approved and actionable molecular biomarkers for colorectal cancer. Additional biomarkers are also described and can be helpful in different image-guided hepatic directed therapies specifically for CRLM. For example, tumors maintaining the Ki-67 proliferation marker after thermal ablation have been particularly resilient to ablation. Ablation margin was also shown to be an important factor in predicting local recurrence, with a ≥10 mm minimal ablation margin being required to attain local tumor control, especially for patients with mutant KRAS CRLM. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

Other

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14 pages, 859 KiB

Open AccessSystematic Review

Antitumor Activity of Metformin Combined with Locoregional Therapy for Liver Cancer: Evidence and Future Directions

by Eshani J. Choksi, Mohammad Elsayed and Nima Kokabi

Cancers 2023, 15(18), 4538; https://doi.org/10.3390/cancers15184538 - 13 Sep 2023

Cited by 1 | Viewed by 1390

Abstract

This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to [...] Read more.

This article aimed to examine the effect of metformin use on improving outcomes after liver-directed therapy in patients with HCC and identify future directions with the adjuvant use of and potential therapeutic agents that operate on similar mechanistic pathways. Databases were queried to identify pertinent articles on metformin’s use as an anti-cancer agent in HCC. Eleven studies were included, with five pre-clinical and six clinical studies. The mean overall survival (OS) and progression-free survival were both higher in the locoregional therapy (LRT) + metformin-treated groups. The outcome variables, including local tumor recurrence rate, reduction in HCC tumor growth and size, tumor growth, proliferation, migration and invasion of HCC cells, HCC cell apoptosis, DNA damage, and cell cycle arrest, showed favorable outcomes in the LRT + metformin-treated groups compared with LRT alone. This systemic review provides a strong signal that metformin use can improve the tumor response after locoregional therapy. Well-controlled prospective trials will be needed to elucidate the potential antitumor effects of metformin and other mTOR inhibitors. Full article

(This article belongs to the Special Issue Liver Cancers Molecular Biomarkers Predicting Outcome)

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