Special Issue "Cancer Biomarkers and Targets in Digestive Organs"

A special issue of Biomedicines (ISSN 2227-9059).

Deadline for manuscript submissions: closed (30 April 2018)

Special Issue Editors

Guest Editor
Dr. Nelson Yee

Division of Hematology-Oncology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Program of Experimental Therapeutics, Penn State Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
Website | E-Mail
Interests: pancreatic carcinoma, hepatobiliary carcinoma, gastroesophageal carcinoma, colorectal carcinoma, precision medicine, targeted therapy, immunotherapy
Co-Guest Editor
Dr. Nikki Lee

Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong
Website | E-Mail
Interests: liver cancer; esophageal cancer; biomarker; therapeutic target; imaging

Special Issue Information

Dear Colleagues,

Identification and development of cancer biomarkers and targets have greatly accelerated progress towards precision medicine in oncology. Studies of tumor biology have not only provided insights into the mechanisms underlying carcinogenesis, but also led to discovery of molecules that have been developed into cancer biomarkers and targets. Multi-platforms for molecular characterization of tumors using next-generation genomic sequencing, immunohistochemistry, in situ hybridization, and blood-based biopsies have greatly expanded the portfolio of potential biomarkers and targets. These cancer biomarkers have been developed for diagnosis, early detection, prognosis, and prediction of treatment response. The molecular targets have been exploited for anti-cancer therapy and delivery of therapeutic agents. This Special Issue of Biomedicines focuses on recent advances in the discovery, characterization, translation, and clinical application of cancer biomarkers and targets in malignant diseases of the digestive system. The goal is to stimulate research and clinical interests in this exciting field with the hope of developing strategies for prevention and early detection of cancers in digestive organs, and improving treatment outcomes in patients with these malignant diseases.

Dr. Nelson Yee
Dr. Nikki Lee
Guest Editor

Manuscript Submission Information

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Keywords

  • gastrointestinal oncology
  • biomarkers
  • targets
  • circulating tumor cells
  • extracellular vesicles
  • molecular profiling
  • precision medicine

Published Papers (10 papers)

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Research

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Open AccessArticle Assessing Clinical Outcomes in Colorectal Cancer with Assays for Invasive Circulating Tumor Cells
Biomedicines 2018, 6(2), 69; https://doi.org/10.3390/biomedicines6020069
Received: 10 April 2018 / Revised: 17 May 2018 / Accepted: 1 June 2018 / Published: 6 June 2018
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Abstract
Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from
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Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from 93 patients with Stage I–IV CRC was obtained and assessed for the detection and characterization of iCTCs using a functional collagen-based adhesion matrix (CAM) invasion assay. Patients were followed and assessed for overall survival. Tumor cells isolated by CAM were characterized using cell culture and microarray analyses. Of 93 patients, 88 (95%) had detectable iCTCs, ranging over 0–470 iCTCs/mL. Patients with Stage I–IV disease exhibited median counts of 0.0 iCTCs/mL (n = 6), 13.0 iCTCs/mL (n = 12), 41.0 iCTCs/mL (n = 12), and 133.0 iCTCs/mL (n = 58), respectively (p < 0.001). Kaplan–Meier curve analysis demonstrated a significant survival benefit in patients with low iCTC counts compared with in patients with high iCTC counts (log-rank p < 0.001). Multivariable Cox model analysis revealed that iCTC count was an independent prognostic factor of overall survival (p = 0.009). Disease stage (p = 0.01, hazard ratio 1.66; 95% confidence interval: 1.12–2.47) and surgical intervention (p = 0.03, HR 0.37; 95% CI: 0.15–0.92) were also independent prognostic factors. Gene expression analysis demonstrated the expression of both endothelial and tumor progenitor cell biomarkers in iCTCs. CAM-based invasion assay shows a high detection sensitivity of iCTCs that inversely correlated with overall survival in CRC patients. Functional and gene expression analyses showed the phenotypic mosaics of iCTCs, mimicking the survival capability of circulating endothelial cells in the blood stream. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessArticle Transcriptome Analysis of Acute Phase Liver Graft Injury in Liver Transplantation
Biomedicines 2018, 6(2), 41; https://doi.org/10.3390/biomedicines6020041
Received: 22 December 2017 / Revised: 4 April 2018 / Accepted: 5 April 2018 / Published: 6 April 2018
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Abstract
Background: Liver transplantation remains the treatment of choice for a selected group of hepatocellular carcinoma (HCC) patients. However, the long-term benefit is greatly hampered by post-transplant HCC recurrence. Our previous studies have identified liver graft injury as an acute phase event leading to
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Background: Liver transplantation remains the treatment of choice for a selected group of hepatocellular carcinoma (HCC) patients. However, the long-term benefit is greatly hampered by post-transplant HCC recurrence. Our previous studies have identified liver graft injury as an acute phase event leading to post-transplant tumor recurrence. Methods: To re-examine this acute phase event at the molecular level and in an unbiased way, RNA sequencing (RNA-Seq) was performed on liver graft biopsies obtained from the transplant recipients two hours after portal vein reperfusion with an aim to capture frequently altered pathways that account for post-transplant tumor recurrence. Liver grafts from recurrent recipients (n = 6) were sequenced and compared with those from recipients without recurrence (n = 5). Results: RNA expression profiles comparison pointed to several frequently altered pathways, among which pathways related to cell adhesion molecules were the most involved. Subsequent validation using quantitative polymerase chain reaction confirmed the differential involvement of two cell adhesion molecules HFE (hemochromatosis) and CD274 and their related molecules in the acute phase event. Conclusion: This whole transcriptome strategy unravels the molecular landscape of liver graft gene expression alterations, which can identify key pathways and genes that are involved in acute phase liver graft injury that may lead to post-transplant tumor recurrence. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Review

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Open AccessReview New Development of Biomarkers for Gastrointestinal Cancers: From Neoplastic Cells to Tumor Microenvironment
Biomedicines 2018, 6(3), 87; https://doi.org/10.3390/biomedicines6030087
Received: 5 June 2018 / Revised: 30 July 2018 / Accepted: 10 August 2018 / Published: 13 August 2018
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Abstract
Biomarkers refer to a plethora of biological characteristics that can be quantified to facilitate cancer diagnosis, forecast the prognosis of disease, and predict a response to treatment. The identification of objective biomarkers is among the most crucial steps in the realization of individualized
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Biomarkers refer to a plethora of biological characteristics that can be quantified to facilitate cancer diagnosis, forecast the prognosis of disease, and predict a response to treatment. The identification of objective biomarkers is among the most crucial steps in the realization of individualized cancer care. Several tumor biomarkers for gastrointestinal malignancies have been applied in the clinical setting to help differentiate between cancer and other conditions, facilitate patient selection for targeted therapies, and to monitor treatment response and recurrence. With the coming of the immunotherapy age, the need for a new development of biomarkers that are indicative of the immune response to tumors are unprecedentedly urgent. Biomarkers from the tumor microenvironment, tumor genome, and signatures from liquid biopsies have been explored, but the majority have shown a limited prognostic or predictive value as single biomarkers. Nevertheless, use of multiplex biomarkers has the potential to provide a significantly increased diagnostic accuracy compared to traditional single biomarker. A comprehensive analysis of immune-biomarkers is needed to reveal the dynamic and multifaceted anti-tumor immunity and thus imply for the rational design of assays and combinational strategies. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessReview Utilizing Peptide Ligand GPCRs to Image and Treat Pancreatic Cancer
Biomedicines 2018, 6(2), 65; https://doi.org/10.3390/biomedicines6020065
Received: 15 May 2018 / Accepted: 28 May 2018 / Published: 2 June 2018
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Abstract
It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 74–75). There is an unmet need for reagents
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It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 74–75). There is an unmet need for reagents that can reliably identify early cancerous or precancerous lesions through various imaging modalities or could be employed to deliver anticancer treatments specifically to tumor cells. However, to date, many PDAC tumor-targeting strategies lack selectivity and are unable to discriminate between tumor and nontumor cells, causing off-target effects or unclear diagnoses. Although a variety of approaches have been taken to identify tumor-targeting reagents that can effectively direct therapeutics or imaging agents to cancer cells (Liu, D. et al., J. Controlled Release 2015, 219, 632–643), translating these reagents into clinical practice has been limited, and it remains an area open to new methodologies and reagents (O’Connor, J.P. et al., Nat. Rev. Clin. Oncol. 2017, 14, 169–186). G protein–coupled receptors (GPCRs), which are key target proteins for drug discovery and comprise a large proportion of currently marketed therapeutics, hold significant promise for tumor imaging and targeted treatment, particularly for pancreatic cancer. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessReview Molecular Characterization of Gastric Carcinoma: Therapeutic Implications for Biomarkers and Targets
Biomedicines 2018, 6(1), 32; https://doi.org/10.3390/biomedicines6010032
Received: 1 January 2018 / Revised: 11 February 2018 / Accepted: 5 March 2018 / Published: 9 March 2018
Cited by 2 | PDF Full-text (805 KB) | HTML Full-text | XML Full-text
Abstract
Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker
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Palliative chemotherapy is the mainstay of treatment of advanced gastric carcinoma (GC). Monoclonal antibodies including trastuzumab, ramucirumab, and pembrolizumab have been shown to provide additional benefits. However, the clinical outcomes are often unpredictable and they can vary widely among patients. Currently, no biomarker is available for predicting treatment response in the individual patient except human epidermal growth factor receptor 2 (HER2) amplification and programmed death-ligand 1 (PD-L1) expression for effectiveness of trastuzumab and pembrolizumab, respectively. Multi-platform molecular analysis of cancer, including GC, may help identify predictive biomarkers to guide selection of therapeutic agents. Molecular classification of GC by The Cancer Genome Atlas Research Network and the Asian Cancer Research Group is expected to identify therapeutic targets and predictive biomarkers. Complementary to molecular characterization of GC is molecular profiling by expression analysis and genomic sequencing of tumor DNA. Initial analysis of patients with gastroesophageal carcinoma demonstrates that the ratio of progression-free survival (PFS) on molecular profile (MP)-based treatment to PFS on treatment prior to molecular profiling exceeds 1.3, suggesting the potential value of MP in guiding selection of individualized therapy. Future strategies aiming to integrate molecular classification and profiling of tumors with therapeutic agents for achieving the goal of personalized treatment of GC are indicated. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessReview Stereotactic Body Radiation Therapy in the Management of Upper GI Malignancies
Received: 8 November 2017 / Revised: 21 December 2017 / Accepted: 23 December 2017 / Published: 3 January 2018
Cited by 1 | PDF Full-text (210 KB) | HTML Full-text | XML Full-text
Abstract
The role of external beam radiation therapy (EBRT) in the management of upper gastrointestinal malignancies is constantly evolving. As radiation therapy techniques improve and are able to deliver more ablative doses of radiotherapy while sparing healthy tissue, radiation can be applied to a
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The role of external beam radiation therapy (EBRT) in the management of upper gastrointestinal malignancies is constantly evolving. As radiation therapy techniques improve and are able to deliver more ablative doses of radiotherapy while sparing healthy tissue, radiation can be applied to a wider range of clinical scenarios. Stereotactic body radiation therapy (SBRT) allows a high dose of radiation to be delivered to a highly conformal treatment volume in a short amount of time. Another potential advantage of SBRT is its ability to increase tumor immunogenicity, while also having less of an immunosuppressive effect on the patient, as compared to conventionally fractionated radiation therapy. In so doing, SBRT may potentiate the effects of immune therapy when the two treatments are combined, thus improving therapeutic outcomes. This article provides an overview of the role of SBRT in the management of upper gastrointestinal GI malignancies and the emerging data on immune biomarkers and SBRT, with a focus on pancreatic and liver cancer. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessReview Innovative Disease Model: Zebrafish as an In Vivo Platform for Intestinal Disorder and Tumors
Biomedicines 2017, 5(4), 58; https://doi.org/10.3390/biomedicines5040058
Received: 13 September 2017 / Revised: 26 September 2017 / Accepted: 29 September 2017 / Published: 29 September 2017
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Abstract
Colorectal cancer (CRC) is one of the world’s most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high
[...] Read more.
Colorectal cancer (CRC) is one of the world’s most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high in red meat and over-processed meat, having a history of inflammatory bowel disease, and smoking. Previous zebrafish studies have demonstrated that multiple oncogenes and tumor suppressor genes can be regulated through genetic or epigenetic alterations. Zebrafish research has also revealed that the activation of carcinogenesis-associated signal pathways plays an important role in CRC. The biology of cancer, intestinal disorders caused by carcinogens, and the morphological patterns of tumors have been found to be highly similar between zebrafish and humans. Therefore, the zebrafish has become an important animal model for translational medical research. Several zebrafish models have been developed to elucidate the characteristics of gastrointestinal diseases. This review article focuses on zebrafish models that have been used to study human intestinal disorders and tumors, including models involving mutant and transgenic fish. We also report on xenograft models and chemically-induced enterocolitis. This review demonstrates that excellent zebrafish models can provide novel insights into the pathogenesis of gastrointestinal diseases and help facilitate the evaluation of novel anti-tumor drugs. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Other

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Open AccessConference Report Frontiers in Gastrointestinal Oncology: Advances in Multi-Disciplinary Patient Care
Biomedicines 2018, 6(2), 64; https://doi.org/10.3390/biomedicines6020064
Received: 25 April 2018 / Revised: 9 May 2018 / Accepted: 11 May 2018 / Published: 1 June 2018
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Abstract
Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and
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Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and screening evaluation, treatment modalities, and supportive care for patients with gastrointestinal cancers. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference at the Hershey Country Club in Hershey, Pennsylvania on 29 September 2017, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this oncological specialty. In this continuing medical education-certified conference, updates on the population sciences including health disparities and resistance training were presented. Progress made in various diagnostic evaluation and screening procedures was outlined. New developments in therapeutic modalities in surgical, radiation, and medical oncology were discussed. Cancer genetic testing and counseling and the supportive roles of music and arts in health and cancer were demonstrated. In summary, this disease-focused medical conference highlighted the new frontiers in gastrointestinal oncology, and showcase the multi-disciplinary care provided at the Penn State Cancer Institute. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessCase Report Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study
Biomedicines 2018, 6(2), 46; https://doi.org/10.3390/biomedicines6020046
Received: 13 March 2018 / Revised: 7 April 2018 / Accepted: 9 April 2018 / Published: 17 April 2018
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Abstract
Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA),
[...] Read more.
Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS). Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1) genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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Open AccessConference Report Update in Systemic and Targeted Therapies in Gastrointestinal Oncology
Biomedicines 2018, 6(1), 34; https://doi.org/10.3390/biomedicines6010034
Received: 1 January 2018 / Revised: 28 February 2018 / Accepted: 6 March 2018 / Published: 16 March 2018
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Abstract
Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented
[...] Read more.
Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented. The use of peri-operative chemotherapy comprised of 5-fluorouracil or capecitabine, leucovorin, oxaliplatin, and docetaxel (FLOT), and immunotherapy including pembrolizumab, nivolumab, and ipilimumab in gastroesophageal carcinoma are discussed. Data from clinical trials that investigated the targeted therapeutics including nivolumab, ramucirumab, lenvatinib, and BLU-554 are reported. The role of adjuvant capecitabine in resected biliary tract carcinoma (BTC) and nab-paclitaxel in combination with gemcitabine and cisplatin in advanced BTC are presented. In colorectal carcinoma, the efficacy of nivolumab, adjuvant FOLFOX or CAPOX, irinotecan/cetuximab/vemurafenib, and trifluridine/tipiracil/bevacizumab, is examined. In summary, some of the above systemic therapies have become or are expected to become new standard of care, while the others demonstrate the potential of becoming new treatment options. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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