Cancers

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Open AccessArticle

Cimetidine and Clobenpropit Attenuate Inflammation-Associated Colorectal Carcinogenesis in Male ICR Mice

by Takuji Tanaka, Takahiro Kochi, Yohei Shirakami, Takayuki Mori, Ayumi Kurata, Naoki Watanabe, Hisataka Moriwaki and Masahito Shimizu

Cancers 2016, 8(2), 25; https://doi.org/10.3390/cancers8020025 - 20 Feb 2016

Cited by 26 | Viewed by 6467

Abstract

Histamine and histamine receptors (Hrhs) have been identified as critical molecules during inflammation and carcinogenesis. This study was conducted to determine the effects of Hrh1-Hrh3 antagonists on inflammation-associated colorectal carcinogenesis. Male ICR mice were treated with azoxymethane (AOM, 10 mg/kg bw, i.p.) and [...] Read more.

Histamine and histamine receptors (Hrhs) have been identified as critical molecules during inflammation and carcinogenesis. This study was conducted to determine the effects of Hrh1-Hrh3 antagonists on inflammation-associated colorectal carcinogenesis. Male ICR mice were treated with azoxymethane (AOM, 10 mg/kg bw, i.p.) and 1.5% dextran sodium sulfate (DSS, drinking water for 7 days) to induce colorectal carcinogenesis. The mice were then fed diets containing test chemical (500 ppm terfenadine, 500 ppm cimetidine or 10 ppm clobenpropit) for 15 weeks. At week 18, feeding with the diets containing cimetidine (Hrh2 antagonist) and clobenpropit (Hrh3 antagonist/inverse agonist) significantly lowered the multiplicity of colonic adenocarcinoma. Terfenadine (Hrh1 antagonist) did not affect AOM-DSS-induced colorectal carcinogenesis. Adenocarcinoma cells immunohistochemically expressed Hrh1, Hrh2, Hrh3 and Hrh4 with varied intensities. Because clobenpropit is also known to be a Hrh4 receptor agonist, Hrh2, Hrh3 and Hrh4 may be involved in inflammation-related colorectal carcinogenesis. Additional data, including the mRNA expression of pro-inflammatory cytokines and inducible inflammatory enzymes in the colonic mucosa, are also presented. Full article

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Open AccessReview

The Role of HPV in Head and Neck Cancer Stem Cell Formation and Tumorigenesis

by Mark S. Swanson, Niels Kokot and Uttam K. Sinha

Cancers 2016, 8(2), 24; https://doi.org/10.3390/cancers8020024 - 19 Feb 2016

Cited by 20 | Viewed by 5621

Abstract

The cancer stem cell (CSC) theory proposes that a minority of tumor cells are capable of self-replication and tumorigenesis. It is these minority of cells that are responsible for cancer metastasis and recurrence in head and neck squamous cell cancers (HNSCC). Human papilloma [...] Read more.

The cancer stem cell (CSC) theory proposes that a minority of tumor cells are capable of self-replication and tumorigenesis. It is these minority of cells that are responsible for cancer metastasis and recurrence in head and neck squamous cell cancers (HNSCC). Human papilloma virus (HPV)-related cancer of the oropharynx is becoming more prevalent, which makes understanding of the relationship between HPV and CSCs more important than ever. This relationship is critical because CSC behavior can be predicted based on cell surface markers, which makes them a suitable candidate for targeted therapy. New therapies are an exciting opportunity to advance past the stalled outcomes in HNSCC that have plagued patients and clinicians for several decades. Full article

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Open AccessArticle

Association between Genetic Variants in DNA Double-Strand Break Repair Pathways and Risk of Radiation Therapy-Induced Pneumonitis and Esophagitis in Non-Small Cell Lung Cancer

by Lina Zhao, Xia Pu, Yuanqing Ye, Charles Lu, Joe Y. Chang and Xifeng Wu

Cancers 2016, 8(2), 23; https://doi.org/10.3390/cancers8020023 - 18 Feb 2016

Cited by 10 | Viewed by 4994

Abstract

Radiation therapy (RT)-induced pneumonitis and esophagitis are commonly developed side effects in non-small cell lung cancer (NSCLC) patients treated with definitive RT. Identifying patients who are at increased risk for these toxicities would help to maximize treatment efficacy while minimizing toxicities. Here, we [...] Read more.

Radiation therapy (RT)-induced pneumonitis and esophagitis are commonly developed side effects in non-small cell lung cancer (NSCLC) patients treated with definitive RT. Identifying patients who are at increased risk for these toxicities would help to maximize treatment efficacy while minimizing toxicities. Here, we systematically investigated single nucleotide polymorphisms (SNPs) within double-strand break (DSB) repair pathway as potential predictive markers for radiation-induced esophagitis and pneumonitis. We genotyped 440 SNPs from 45 genes in DSB repair pathways in 250 stage I–III NSCLC patients who received definitive radiation or chemoradiation therapy, followed by internal validation in 170 additional patients. We found that 11 SNPs for esophagitis and 8 SNPs for pneumonitis showed consistent effects between discovery and validation populations (same direction of OR and reached significance in meta-analysis). Among them, rs7165790 in the BLM gene was significantly associated with decreased risk of esophagitis in both discovery (OR = 0.59, 95% CI: 0.37–0.97, p = 0.037) and validation subgroups (OR = 0.45, 95% CI: 0.22–0.94, p = 0.032). A strong cumulative effect was observed for the top SNPs, and gene-based tests revealed 12 genes significantly associated with esophagitis or pneumonitis. Our results support the notion that genetic variations within DSB repair pathway could influence the risk of developing toxicities following definitive RT in NSCLC. Full article

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

294 KiB

Open AccessArticle

Nephrotoxicity as a Dose-Limiting Factor in a High-Dose Cisplatin-Based Chemoradiotherapy Regimen for Head and Neck Carcinomas

by Jantien Hoek, Karen M. Bloemendal, Lilly-Ann A. Van der Velden, Judi N.A. Van Diessen, Erik Van Werkhoven, Willem M.C. Klop and Margot E.T. Tesselaar

Cancers 2016, 8(2), 21; https://doi.org/10.3390/cancers8020021 - 16 Feb 2016

Cited by 57 | Viewed by 6740

Abstract

Purpose: Loco-regional control and organ preservation are significantly improved with concomitant cisplatin/radiotherapy and are compromised with less than 5% grade 3 nephrotoxicity (creatinine clearance 15–29 mL/min). However, although clinically important, in none of the randomized trials is grade 2 nephrotoxicity (defined as [...] Read more.

Purpose: Loco-regional control and organ preservation are significantly improved with concomitant cisplatin/radiotherapy and are compromised with less than 5% grade 3 nephrotoxicity (creatinine clearance 15–29 mL/min). However, although clinically important, in none of the randomized trials is grade 2 nephrotoxicity (defined as creatinine clearance 59–30 mL/min) mentioned. In this study, we assessed nephrotoxicity in daily practice among patients treated with high-dose cisplatin (100 mg/m² on days 1, 22, and 43), concurrently with chemoradiotherapy (CCRT) and the impact on treatment modifications. Methods: 208 patients with advanced-stage malignancies of the head and neck region were evaluated. All patients were treated with high-dose cisplatin CCRT. The main outcome parameters were nephrotoxicity (defined as creatinine clearance grade 2 or more) and cumulative doses of cisplatin and radiation. Results: 133 patients (64%) completed all pre-planned courses of cisplatin. Nephrotoxicity was the main reason to discontinue the chemotherapy. Grade 3 nephrotoxicity was seen in 16 patients (8%) while grade 2 nephrotoxicity was seen in 53 patients (25%). Thirty six patients (17%) could not complete the pre-planned chemotherapy due to nephrotoxicity. Conclusions: In head and neck cancer patients, nephrotoxicity grade 2 is under-reported but is the major factor for discontinuing cisplatin during CCRT. Full article

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Open AccessReview

Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

by Tadas K. Rimkus, Richard L. Carpenter, Shadi Qasem, Michael Chan and Hui-Wen Lo

Cancers 2016, 8(2), 22; https://doi.org/10.3390/cancers8020022 - 15 Feb 2016

Cited by 473 | Viewed by 44368

Abstract

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers [...] Read more.

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials. Full article

(This article belongs to the Special Issue Hedgehog Signaling Pathway in Cancer: Smoothened and GLI Take Center Stage)

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Open AccessArticle

Conditional Melanoma Cancer Survival in the United States

by Ray M. Merrill and Simone Bateman

Cancers 2016, 8(2), 20; https://doi.org/10.3390/cancers8020020 - 2 Feb 2016

Cited by 19 | Viewed by 5832

Abstract

Beyond relative survival, which indicates the likelihood that patients will not die from causes associated with their cancer, conditional relative survival probabilities provide further useful prognostic information to cancer patients, tailored to the time already survived from diagnosis. This study presents conditional relative [...] Read more.

Beyond relative survival, which indicates the likelihood that patients will not die from causes associated with their cancer, conditional relative survival probabilities provide further useful prognostic information to cancer patients, tailored to the time already survived from diagnosis. This study presents conditional relative survival for melanoma patients in the United States, diagnosed during 2000–2008 and followed through 2012. Analyses are based on 62,803 male and 50,261 female cases in population-based cancer registries in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Five-year relative survival estimates are presented for melanoma patients who have already survived one, two, three, four, or five years after the initial diagnosis. Five- and ten-year relative survival decreases with age, stage at diagnosis, and is lower among males, Blacks, and Hispanics. Five-year conditional relative survival improves with each year already survived. The potential for improvement in five-year conditional relative survival is greatest for older age, males, Blacks, Hispanics, and in later staged cases. For local disease, five-year conditional relative survival was significantly lower in ages greater than 65 years and in Blacks. It was significantly higher in females, non-Hispanics, and married individuals. Age had a greater inverse relationship with five-year survival in later staged disease. A similar result occurred for females and married individuals. In contrast, non-Hispanics had better five-year survival if diagnosed with local or regional disease, but not distant disease. Full article

(This article belongs to the Special Issue Current Topics in Cutaneous Melanoma)

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Open AccessReview

Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go

by Rachel J. Buchsbaum and Sun Young Oh

Cancers 2016, 8(2), 19; https://doi.org/10.3390/cancers8020019 - 27 Jan 2016

Cited by 141 | Viewed by 9522

Abstract

Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular [...] Read more.

Cancers are heterogeneous tissues comprised of multiple components, including tumor cells and microenvironment cells. The tumor microenvironment has a critical role in tumor progression. The tumor microenvironment is comprised of various cell types, including fibroblasts, macrophages and immune cells, as well as extracellular matrix and various cytokines and growth factors. Fibroblasts are the predominant cell type in the tumor microenvironment. However, neither the derivation of tissue-specific cancer-associated fibroblasts nor markers of tissue-specific cancer-associated fibroblasts are well defined. Despite these uncertainties it is increasingly apparent that cancer-associated fibroblasts have a crucial role in tumor progression. In breast cancer, there is evolving evidence showing that breast cancer-associated fibroblasts are actively involved in breast cancer initiation, proliferation, invasion and metastasis. Breast cancer-associated fibroblasts also play a critical role in metabolic reprogramming of the tumor microenvironment and therapy resistance. This review summarizes the current understanding of breast cancer-associated fibroblasts. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts)

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Cancers, Volume 8, Issue 2 (February 2016) – 7 articles

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