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24 pages, 3293 KiB

Open AccessArticle

New Insights on Old Biomarkers Involved in Tumor Microenvironment Changes and Their Diagnostic Relevance in Non-Small Cell Lung Carcinoma

by Katarzyna Wadowska, Piotr Błasiak, Adam Rzechonek, Iwona Bil-Lula and Mariola Śliwińska-Mossoń

Biomolecules 2021, 11(8), 1208; https://doi.org/10.3390/biom11081208 - 13 Aug 2021

Cited by 9 | Viewed by 3654

Abstract

Background: Lung cancer is a multifactorial disease with a heterogeneous tumor group that hampers diagnostic and therapeutic approaches, as well as understanding of the processes that underlie its pathogenesis. Current research efforts are focused on examining alterations in the tumor microenvironment, which may [...] Read more.

Background: Lung cancer is a multifactorial disease with a heterogeneous tumor group that hampers diagnostic and therapeutic approaches, as well as understanding of the processes that underlie its pathogenesis. Current research efforts are focused on examining alterations in the tumor microenvironment, which may affect the pathogenesis and further malignant progression in lung cancer. The aim of this study was to investigate changes in the levels of biomarkers involved in the lung tumor microenvironment and their diagnostic utility in differentiating lung cancer subtypes and stages. Methods: This study comprised 112 lung cancer patients, 50 with adenocarcinoma, 35 with squamous cell carcinoma, 13 with other non-small cell lung carcinoma subtypes, and 14 with other lung neoplasms than non-small cell lung carcinoma. Tumor markers (CEA, CYFRA 21-1, and NSE) were measured in the patients’ sera and plasmas, along with IL-6, TNF-α, SAA₁, CRP, MMP-2, MMP-9, glucose, lactate, and LDH, utilizing enzyme-linked immunosorbent assays, enzyme immunoassays, and automated clinical chemistry and turbidimetry systems. The results were statistically analyzed across patient groups based on the subtype and stage of lung cancer. Results: Glucose concentrations showed statistically significant (p < 0.05) differences both between lung cancer subtypes and stages, with the highest levels in patients with other lung neoplasms (me = 130.5 mg/dL) and in patients with stage IIB lung cancer (me = 132.0 mg/dL). In patients with advanced lung cancer, IL-6 and LDH had considerably higher concentration and activity. There was also a significant positive correlation between IL-6 and MMP-9 in adenocarcinoma and SqCC, with correlation coefficients of 0.53 and 0.49, respectively. The ROC analyses showed that the best single biomarkers for distinguishing adenocarcinoma from squamous cell carcinoma are glucose, CRP, and CYFRA 21-1; however, their combination did not significantly improve sensitivity, specificity, and the AUC value. The combinations of IL-6, glucose, LDH and CEA, IL-6, SAA1, MMP-9, and lactate can distinguish patients with stage IIB lung cancer from those with stage IIA with 100% sensitivity, 100% specificity, and with an AUC value of 0.8333 and 1.0000, respectively, whereas the combination of CEA, IL-6, and LDH can identify patients with stage IIIA lung cancer from those with stage IIB with 72.73% sensitivity, 94.44% specificity, and an AUC value of 0.8686. Conclusion: There is a link between biomarkers of tumor microenvironment changes and tumor markers, and combinations of these markers may be clinically useful in the differential diagnosis of adenocarcinoma and squamous cell carcinoma, as well as lung cancer stages IIB and IIA, and IIIA and IIB. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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Review

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39 pages, 1315 KiB

Open AccessReview

Molecular Biomarkers in Cancer

by Virinder Kaur Sarhadi and Gemma Armengol

Biomolecules 2022, 12(8), 1021; https://doi.org/10.3390/biom12081021 - 23 Jul 2022

Cited by 169 | Viewed by 14291

Abstract

Molecular cancer biomarkers are any measurable molecular indicator of risk of cancer, occurrence of cancer, or patient outcome. They may include germline or somatic genetic variants, epigenetic signatures, transcriptional changes, and proteomic signatures. These indicators are based on biomolecules, such as nucleic acids [...] Read more.

Molecular cancer biomarkers are any measurable molecular indicator of risk of cancer, occurrence of cancer, or patient outcome. They may include germline or somatic genetic variants, epigenetic signatures, transcriptional changes, and proteomic signatures. These indicators are based on biomolecules, such as nucleic acids and proteins, that can be detected in samples obtained from tissues through tumor biopsy or, more easily and non-invasively, from blood (or serum or plasma), saliva, buccal swabs, stool, urine, etc. Detection technologies have advanced tremendously over the last decades, including techniques such as next-generation sequencing, nanotechnology, or methods to study circulating tumor DNA/RNA or exosomes. Clinical applications of biomarkers are extensive. They can be used as tools for cancer risk assessment, screening and early detection of cancer, accurate diagnosis, patient prognosis, prediction of response to therapy, and cancer surveillance and monitoring response. Therefore, they can help to optimize making decisions in clinical practice. Moreover, precision oncology is needed for newly developed targeted therapies, as they are functional only in patients with specific cancer genetic mutations, and biomarkers are the tools used for the identification of these subsets of patients. Improvement in the field of cancer biomarkers is, however, needed to overcome the scientific challenge of developing new biomarkers with greater sensitivity, specificity, and positive predictive value. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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14 pages, 300 KiB

Open AccessReview

Flow Cytometric Detection of Malignant Blasts in Cerebrospinal Fluid: A Biomarker of Central Nervous System Involvement in Childhood Acute Lymphoblastic Leukemia

by Maria Thastrup, Hanne Vibeke Marquart and Kjeld Schmiegelow

Biomolecules 2022, 12(6), 813; https://doi.org/10.3390/biom12060813 - 9 Jun 2022

Cited by 8 | Viewed by 3386

Abstract

Despite the excellent prognosis for children and adolescents with acute lymphoblastic lymphoma (ALL), the involvement of the central nervous system (CNS) represents a major therapeutic challenge. Patients who develop CNS relapse have a very poor prognosis, and since current methods cannot reliably identify [...] Read more.

Despite the excellent prognosis for children and adolescents with acute lymphoblastic lymphoma (ALL), the involvement of the central nervous system (CNS) represents a major therapeutic challenge. Patients who develop CNS relapse have a very poor prognosis, and since current methods cannot reliably identify patients with CNS involvement or patients at high risk of CNS relapse, all children with ALL receive CNS-directed treatment. The current golden standard for detecting CNS involvement is the assessment of cytomorphology on cytospin slides of cerebrospinal fluid (CSF). This technique is inadequate due to low sensitivity and reproducibility. Flow cytometric analysis of CSF represent a novel, highly specific and sensitive technique for the detection of leukemic cells in the CNS. In prospective studies, CSF flow cytometry demonstrated two to three times higher rates of CNS involvement at diagnosis of childhood ALL than conventional cytospin, and especially demonstrated superior sensitivity in detecting low-level CNS disease. CNS involvement determined via flow cytometry has been linked to a higher risk of CNS relapse and poor outcomes in several studies. In this review, we discuss the central analytical concepts of CSF flow cytometry and summarize the current evidence supporting the use of flow cytometric detection of malignant blasts as a biomarker of CNS involvement in childhood ALL. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

22 pages, 410 KiB

Open AccessReview

Oncogenomic Changes in Pancreatic Cancer and Their Detection in Stool

by Heidelinde Sammallahti, Virinder Kaur Sarhadi, Arto Kokkola, Reza Ghanbari, Sama Rezasoltani, Hamid Asadzadeh Aghdaei, Pauli Puolakkainen and Sakari Knuutila

Biomolecules 2022, 12(5), 652; https://doi.org/10.3390/biom12050652 - 29 Apr 2022

Cited by 7 | Viewed by 3616

Abstract

Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be [...] Read more.

Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

22 pages, 879 KiB

Open AccessReview

Endocan in Acute Leukemia: Current Knowledge and Future Perspectives

by Håkon Reikvam, Kimberley Joanne Hatfield, Øystein Wendelbo, Roald Lindås, Philippe Lassalle and Øystein Bruserud

Biomolecules 2022, 12(4), 492; https://doi.org/10.3390/biom12040492 - 24 Mar 2022

Cited by 2 | Viewed by 2611

Abstract

Endocan is a soluble dermatan sulfate proteoglycan expressed by endothelial cells and detected in serum/plasma. Its expression is increased in tumors/tumor vessels in several human malignancies, and high expression (high serum/plasma levels or tumor levels) has an adverse prognostic impact in several malignancies. [...] Read more.

Endocan is a soluble dermatan sulfate proteoglycan expressed by endothelial cells and detected in serum/plasma. Its expression is increased in tumors/tumor vessels in several human malignancies, and high expression (high serum/plasma levels or tumor levels) has an adverse prognostic impact in several malignancies. The p14 endocan degradation product can also be detected in serum/plasma, but previous clinical studies as well as previously unpublished results presented in this review suggest that endocan and p14 endocan fragment levels reflect different biological characteristics, and the endocan levels seem to reflect the disease heterogeneity in acute leukemia better than the p14 fragment levels. Furthermore, decreased systemic endocan levels in previously immunocompetent sepsis patients are associated with later severe respiratory complications, but it is not known whether this is true also for immunocompromised acute leukemia patients. Finally, endocan is associated with increased early nonrelapse mortality in (acute leukemia) patients receiving allogeneic stem cell transplantation, and this adverse prognostic impact seems to be independent of the adverse impact of excessive fluid overload. Systemic endocan levels may also become important to predict cytokine release syndrome after immunotherapy/haploidentical transplantation, and in the long-term follow-up of acute leukemia survivors with regard to cardiovascular risk. Therapeutic targeting of endocan is now possible, and the possible role of endocan in acute leukemia should be further investigated to clarify whether the therapeutic strategy should also be considered. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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16 pages, 10206 KiB

Open AccessReview

Androgen Receptor as an Emerging Feasible Biomarker for Breast Cancer

by Chan-Ping You, Man-Hong Leung, Wai-Chung Tsang, Ui-Soon Khoo and Ho Tsoi

Biomolecules 2022, 12(1), 72; https://doi.org/10.3390/biom12010072 - 4 Jan 2022

Cited by 27 | Viewed by 5061

Abstract

Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone [...] Read more.

Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone receptor, contributes to the development and progression of prostate tumors and other cancers. With increasing evidence to support that AR plays an essential role in breast cancer, AR has been considered a useful biomarker in breast cancer, depending on the context of breast cancer sub-types. The existing survival analyses suggest that AR acts as a tumor suppressor in ER + ve breast cancers, serving as a favorable prognostic marker. However, AR functions as a tumor promoter in ER-ve breast cancers, including HER2 + ve and triple-negative (TNBC) breast cancers, serving as a poor prognostic factor. AR has also been shown to be predictive of the potential of response to adjuvant hormonal therapy in ER + ve breast cancers and to neoadjuvant chemotherapy in TNBC. However, conflicting results do exist due to intrinsic molecular differences between tumors and the scoring method for AR positivity. Applying AR expression status to guide treatment in different breast cancer sub-types has been suggested. In the future, AR will be a feasible biomarker for breast cancer. Clinical trials using AR antagonists in breast cancer are active. Targeting AR alone or other therapeutic agents provides alternatives to existing therapy for breast cancer. Therefore, AR expression will be necessary if AR-targeted treatment is to be used. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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32 pages, 2394 KiB

Open AccessReview

CD44: A Multifunctional Mediator of Cancer Progression

by Malak Hassn Mesrati, Saiful Effendi Syafruddin, M. Aiman Mohtar and Amir Syahir

Biomolecules 2021, 11(12), 1850; https://doi.org/10.3390/biom11121850 - 9 Dec 2021

Cited by 210 | Viewed by 14146

Abstract

CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- [...] Read more.

CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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20 pages, 618 KiB

Open AccessReview

Novel Methylation Biomarkers for Colorectal Cancer Prognosis

by Alvaro Gutierrez, Hannah Demond, Priscilla Brebi and Carmen Gloria Ili

Biomolecules 2021, 11(11), 1722; https://doi.org/10.3390/biom11111722 - 19 Nov 2021

Cited by 27 | Viewed by 4275

Abstract

Colorectal cancer (CRC) comprises the third most common cancer worldwide and the second regarding number of deaths. In order to make a correct and early diagnosis to predict metastasis formation, biomarkers are an important tool. Although there are multiple signaling pathways associated with [...] Read more.

Colorectal cancer (CRC) comprises the third most common cancer worldwide and the second regarding number of deaths. In order to make a correct and early diagnosis to predict metastasis formation, biomarkers are an important tool. Although there are multiple signaling pathways associated with cancer progression, the most recognized are the MAPK pathway, p53 pathway, and TGF-β pathway. These pathways regulate many important functions in the cell, such as cell cycle regulation, proliferation, differentiation, and metastasis formation, among others. Changes in expression in genes belonging to these pathways are drivers of carcinogenesis. Often these expression changes are caused by mutations; however, epigenetic changes, such as DNA methylation, are increasingly acknowledged to play a role in the deregulation of oncogenic genes. This makes DNA methylation changes an interesting biomarkers in cancer. Among the newly identified biomarkers for CRC metastasis INHBB, SMOC2, BDNF, and TBRG4 are included, all of which are highly deregulated by methylation and closely associated with metastasis. The identification of such biomarkers in metastasis of CRC may allow a better treatment and early identification of cancer formation in order to perform better diagnostics and improve the life expectancy. Full article

(This article belongs to the Special Issue Biomarkers in Cancer)

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