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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 28633

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Prof. Dr. Tanja Langsenlehner

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Guest Editor

Department of Therapeutic Radiology and Oncology, Comprehensive Cancer Center, Medical University of Graz, 8036 Graz, Austria
Interests: radiation oncology; prostate cancer; breast cancer; radiogenomics; genetic predisposition to neoplastic diseases; inflammation; biomarkers; prognostic/predictive parameters

Special Issue Information

Dear Colleagues,

Systemic inflammation plays a major role in the pathogenesis and progression of numerous malignancies. Approximately 15–20% of all cancer cases have been linked to chronic inflammatory diseases, including Helicobacter pylori-related gastric disease, autoimmune diseases such as inflammatory bowel disease, and chronic hepatitis. Inflammation may promote carcinogenesis through multiple pathways and has been associated with tumor initiation via the induction of epigenetic or genetic alterations, and with malignant progression through remodeling of the tumor microenvironment.

C-reactive protein (CRP) is an acute-phase protein predominantly synthesized by hepatocytes in response to systemic inflammation. Several studies have revealed a relationship between elevated CRP levels and poor prognosis in various types of cancer. Elevated CRP levels have been suggested to reflect a microenvironment that favors tumor angiogenesis, proliferation, and metastatic dissemination. CRP has also been found to promote tumor growth and survival by enhancing tumor cell proliferation and protecting tumor cells from drug-induced apoptosis.

In this Special Issue, we will publish reviews and original research articles that focus on the predictive and prognostic role of CRP. Novel insights into the stimulation of CRP expression and its function in the modulation of cancer progression are particularly welcome.

Prof. Dr. Tanja Langsenlehner
Guest Editor

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Keywords

Cancer
Inflammation
CRP
Prognostic/predictive factor
Tumor microenvironment
Cell signaling

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Published Papers (7 papers)

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Research

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11 pages, 1007 KiB

Open AccessArticle

Prognostic Biomarkers of Salvage Chemotherapy Following Nivolumab Treatment for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

by Takahiro Wakasaki, Ryuji Yasumatsu, Muneyuki Masuda, Toranoshin Takeuchi, Tomomi Manako, Mioko Matsuo, Rina Jiromaru, Ryutaro Uchi, Noritaka Komune, Teppei Noda and Takashi Nakagawa

Cancers 2020, 12(8), 2299; https://doi.org/10.3390/cancers12082299 - 15 Aug 2020

Cited by 29 | Viewed by 3676

Abstract

Recent studies have suggested the benefit of salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). We retrospectively examined the outcome of SCT and the usefulness of the serum C-reactive protein level (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Thirty-nine patients with R/M HNSCC were enrolled in this study. Twenty-five patients (64.1%) received combination chemotherapy of weekly paclitaxel and cetuximab (PC) as SCT, and 14 patients (35.9%) received tegafur-gimestat-otastat potassium (S1), an oral fluoropyrimidine. In all patients, the response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 45.2%, 85.7%, 6.5 months, and 13.5 months, respectively. No chemotherapy-related deaths were observed. These PC groups had low CRP (<1.2 mg/dL) or low NLR (<7.0) values at the time of SCT induction, which was significantly associated with an improved OS (p = 0.0440, p = 0.0354). A multivariate analysis also showed that a lower CRP value was significantly associated with a better OS (p = 0.0078). We clarified the usefulness of the PC and S1 regimens as SCT. In addition, SCT with the PC regimen showed a better prognosis with a lower CRP or NLR at induction than a higher CRP or NLR. This is the first report on biomarkers of SCT in R/M HNSCC. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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18 pages, 1720 KiB

Open AccessArticle

The Biological Context of C-Reactive Protein as a Prognostic Marker in Renal Cell Carcinoma: Studies on the Acute Phase Cytokine Profile

by Helene Hersvik Aarstad, Gigja Guðbrandsdottir, Karin M. Hjelle, Leif Bostad, Øystein Bruserud, Tor Henrik Anderson Tvedt and Christian Beisland

Cancers 2020, 12(7), 1961; https://doi.org/10.3390/cancers12071961 - 19 Jul 2020

Cited by 10 | Viewed by 3190

Abstract

High serum levels of the acute phase protein C-reactive protein (CRP) are associated with an adverse prognosis in renal cancer. The acute phase reaction is cytokine-driven and includes a wide range of inflammatory mediators. This overall profile of the response depends on the inducing event and can also differ between patients. We investigated an extended acute phase cytokine profile for 97 renal cancer patients. Initial studies showed that the serum CRP levels had an expected prognostic association together with tumor size, stage, nuclear grading, and Leibovich score. Interleukin (IL)6 family cytokines, IL1 subfamily mediators, and tumor necrosis factor (TNF)α can all be drivers of the acute phase response. Initial studies suggested that serum IL33Rα (the soluble IL33 receptor α chain) levels were also associated with prognosis, although the impact of IL33Rα is dependent on the overall cytokine profile, including seven IL6 family members (IL6, IL6Rα, gp130, IL27, IL31, CNTF, and OSM), two IL1 subfamily members (IL1RA and IL33Rα), and TNFα. We identified a patient subset characterized by particularly high levels of IL6, IL33Rα, and TNFα alongside an adverse prognosis. Thus, the acute phase cytokine reaction differs between renal cancer patients, and differences in the acute phase cytokine profile are associated with prognosis. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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19 pages, 2409 KiB

Open AccessArticle

The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers

by Alexander Rühle, Erik Haehl, Hélène David, Tobias Kalckreuth, Tanja Sprave, Raluca Stoian, Constantinos Zamboglou, Eleni Gkika, Andreas Knopf, Anca-Ligia Grosu and Nils Henrik Nicolay

Cancers 2020, 12(6), 1698; https://doi.org/10.3390/cancers12061698 - 26 Jun 2020

Cited by 18 | Viewed by 3190

Abstract

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan–Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, p < 0.05), a GFR ≤ 60 mL/min/1.73 m² (HR = 1.537, p < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, p < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, p < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, p < 0.05) and baseline albumin (HR = 2.305, p < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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17 pages, 3148 KiB

Open AccessArticle

Systemic Inflammation and Activation of Haemostasis Predict Poor Prognosis and Response to Chemotherapy in Patients with Advanced Lung Cancer

by Florian Moik, Sabine Zöchbauer-Müller, Florian Posch, Ingrid Pabinger and Cihan Ay

Cancers 2020, 12(6), 1619; https://doi.org/10.3390/cancers12061619 - 18 Jun 2020

Cited by 30 | Viewed by 3279

Abstract

Systemic inflammation and activation of haemostasis are common in patients with lung cancer. Both conditions support tumour growth and metastasis. Therefore, inflammatory and haemostatic biomarkers might be useful for prediction of survival and therapy response. Patients with unresectable/metastatic lung cancer initiating 1st-line chemotherapy (n = 277, 83% non-small cell lung cancer) were followed in a prospective observational cohort study. A comprehensive panel of haemostatic biomarkers (D-dimer, prothrombin fragment 1+2, soluble P-selectin, fibrinogen, coagulation factor VIII, peak thrombin generation), blood count parameters (haemoglobin, leucocytes, thrombocytes) and inflammatory markers (neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, platelet-lymphocyte ratio, C-reactive protein) were measured at baseline. We assessed the association of biomarkers with mortality, progression-free-survival (PFS) and disease-control-rate (DCR). A biomarker-based prognostic model was derived. Selected inflammatory and haemostatic biomarkers were strong and independent predictors of mortality and therapy response. The strongest predictors (D-dimer, LMR, CRP) were incorporated in a unified biomarker-based prognostic model (1-year overall-survival (OS) by risk-quartiles: 79%, 69%, 51%, 24%; 2-year-OS: 53%, 36%, 23%, 8%; log-rank p < 0.001). The biomarker-based model further predicted shorter PFS and lower DCR. In conclusion, inflammatory and haemostatic biomarkers predict poor prognosis and treatment-response in patients with advanced lung cancer. A biomarker-based prognostic score efficiently predicts mortality and disease progression beyond clinical characteristics. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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14 pages, 797 KiB

Open AccessArticle

The Pre-Treatment C-Reactive Protein Represents a Prognostic Factor in Patients with Oral and Oropharyngeal Cancer Treated with Radiotherapy

by Olivia Knittelfelder, Daniela Delago, Gabriele Jakse, Katarzyna Lukasiak, Eva-Maria Thurner, Dietmar Thurnher, Martin Pichler, Wilfried Renner, Heidi Stranzl-Lawatsch and Tanja Langsenlehner

Cancers 2020, 12(3), 626; https://doi.org/10.3390/cancers12030626 - 8 Mar 2020

Cited by 13 | Viewed by 3251

Abstract

The purpose of the present study was to evaluate the prognostic significance of the pre- treatment C-reactive protein (CRP) level in a cohort of 503 patients with oral and oropharyngeal cancer treated at a tertiary academic center between 2000 and 2017. Cancer-specific survival (CSS), overall survival (OS) and loco-regional control (LC) were calculated using Kaplan-Meier analysis. To evaluate the prognostic value of the CRP level for the clinical endpoints, univariate and multivariate Cox regression models were applied. The median follow-up period was 61 months. Patients were divided into elevated CRP (≥5 mg/L) and normal CRP groups, according to pre-treatment plasma levels. An increased CRP level was significantly associated with shorter CSS (p < 0.001, log-rank test), as well as with shorter OS (p < 0.001, log-rank test) and loco-regional control (p = 0.001, log-rank test). In addition, multivariate analysis identified CRP as an independent predictor for CSS (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.08–2.35; p = 0.020) as well as for OS (HR 1.62, 95%CI 1.17–2.24; p = 0.004) and LC (HR 1.50, 95%CI 1.06–2.14; p = 0.023). In subgroup analysis, Kaplan Meier curves revealed that an elevated pre-treatment CRP level was a consistent prognostic factor for poor CSS (p = 0.003, log-rank test), OS (p = 0.001, log-rank test), and LC (p = 0.028, log-rank test) in patients treated with definitive (chemo-) radiotherapy, whereas a significant association in patients undergoing surgery and postoperative radiotherapy was not detected. The pre-treatment CRP level seems to represent a prognostic factor for CSS, OS, and LC in patients with oral and oropharyngeal cancer, particularly in those treated with definitive (chemo-) radiotherapy. Additional large-scale prospective studies are warranted to confirm and extend our findings. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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13 pages, 718 KiB

Open AccessFeature PaperArticle

Prediction of Postoperative Clinical Outcomes in Resected Stage I Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score

by Joerg Lindenmann, Nicole Fink-Neuboeck, Valentin Taucher, Martin Pichler, Florian Posch, Luka Brcic, Elisabeth Smolle, Stephan Koter, Josef Smolle and Freyja Maria Smolle-Juettner

Cancers 2020, 12(1), 152; https://doi.org/10.3390/cancers12010152 - 8 Jan 2020

Cited by 16 | Viewed by 3077

Abstract

Background: The Glasgow Prognostic Score (GPS), which consists of albumin and C-reactive protein (CRP), may predict overall survival (OS) in cancer patients. The aim of this retrospective analysis was to evaluate the clinical impact of the preoperative GPS on patients with resected early stage non-small cell lung cancer (NSCLC). Methods: 300 patients with curatively resected stage I NSCLC were followed-up for OS, recurrence-free survival (RFS), cancer-specific survival (CSS), and death from other causes. Results: 229 patients (76%) had a preoperative GPS of 0, and 71 (24%) a GPS ≥ 1. The three-year probabilities of RFS, OS, CSS, and death from other causes were 81%, 84%, 88%, and 96% in patients with GPS = 0, and 79%, 74%, 91%, and 82% in patients with a GPS ≥ 1, respectively. GPS ≥ 1 was significantly associated with a higher risk of death from other causes (p = 0.022), serving as an independent predictor of death from other causes (p = 0.034). Pathologically elevated CRP levels (CRP > 5 mg/L) were found in 91 patients (30%). The mean CRP level was 7.88 ± 15.80 mg/L (0.5–135.6 mg/L). Pre-treatment CRP level was significantly associated with coronary heart disease (p < 0.0001), histology (p = 0.013), tumor size (p = 0.018), tumor stage (p = 0.002), and vascular invasion (p = 0.017). Conclusion: The preoperative GPS predicts adverse survival outcomes in patients with resected stage I NSCLC. Full article

(This article belongs to the Special Issue C-Reactive Protein in Cancer)

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Review

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23 pages, 300 KiB

Open AccessReview

Combined C-Reactive Protein and Novel Inflammatory Parameters as a Predictor in Cancer—What Can We Learn from the Hematological Experience?

by Øystein Bruserud, Helene Hersvik Aarstad and Tor Henrik Anderson Tvedt

Cancers 2020, 12(7), 1966; https://doi.org/10.3390/cancers12071966 - 19 Jul 2020

Cited by 45 | Viewed by 4369

Abstract

The acute phase reaction is a systemic response to acute or chronic inflammation. The serum level of C-reactive protein (CRP) is the only acute phase biomarker widely used in routine clinical practice, including its uses for prognostics and therapy monitoring in cancer patients. Although Interleukin 6 (IL6) is a main trigger of the acute phase reactions, a series of acute phase reactants can contribute (e.g., other members in IL6 family or IL1 subfamily, and tumor necrosis factor α). However, the experience from patients receiving intensive chemotherapy for hematological malignancies has shown that, besides CRP, other biomarkers (e.g., cytokines, soluble cytokine receptors, soluble adhesion molecules) also have altered systemic levels as a part of the acute phase reaction in these immunocompromised patients. Furthermore, CRP and white blood cell counts can serve as a dual prognostic predictor in solid tumors and hematological malignancies. Recent studies also suggest that biomarker profiles as well as alternative inflammatory mediators should be further developed to optimize the predictive utility in cancer patients. Finally, the experience from allogeneic stem cell transplantation suggests that selected acute phase reactants together with specific markers of organ damages are useful for predicting or diagnosing graft versus host disease. Acute phase proteins may also be useful to identify patients (at risk of) developing severe immune-mediated toxicity after anticancer immunotherapy. To conclude, future studies of acute phase predictors in human malignancies should not only investigate the conventional inflammatory mediators (e.g., CRP, white blood cell counts) but also combinations of novel inflammatory parameters with specific markers of organ damages. Full article

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