The Leader Position of Mesenchymal Cells Expressing N-Cadherin in the Collective Migration of Epithelial Cancer

Understanding how heterogeneous cancer cell populations migrate collectively is of paramount importance to arrest metastasis. Here, we applied 3D culture-based approaches for in vitro modeling of the collective migration of squamous carcinoma cells and examine the impact of epithelial and mesenchymal cell interactions on this type of migration. We show that both mesenchymal N-cadherin-expressing cancer cells and cancer-associated fibroblasts cooperate in collective migration of epithelial cancer cells by leading their collective migration. This was consistent with the observed distribution of E-cadherin/N-cadherin in the human carcinoma tissues of head and neck. The presence of “leader” mesenchymal cancer cells or “leader” fibroblasts was significantly associated with metastasis development, recurrent disease and low overall disease survival in head and neck squamous cell carcinomas (HNSCC). In silico analysis of independent public datasets revealed that increased N-cadherin expression in the heterogeneous cancer tissues is associated with disease progression not only in HNSCC but also in other prevalent tumors, such as colorectal, breast and lung cancer. Collectively, our data highlight the importance of mesenchymal cells in collective cell migration and disease progression, findings that may have a broad significance in cancer, especially in those in which aberrant N-cadherin expression negatively impacts disease survival.

Download Full-text

Cancer-Associated Fibroblast Subgroups Showing Differential Promoting Effect on HNSCC Progression

Cancers ◽

10.3390/cancers13040654 ◽

2021 ◽

Vol 13 (4) ◽

pp. 654

Author(s):

Soo Hyun Kang ◽

Su Young Oh ◽

Heon-Jin Lee ◽

Tae-Geon Kwon ◽

Jin-Wook Kim ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Cancer Cells ◽

Microarray Analysis ◽

Dna Microarray ◽

Epithelial Cancer ◽

Matrigel Invasion ◽

Cancer Associated Fibroblast ◽

Cancer Tissues

Background: The critical effect of the tumor microenvironment on cancer progression is well recognized. Recent research suggests that the cancer-promoting properties of the tumor stroma may be attributed to fibroblasts. However, the effect of cancer-associated fibroblast (CAF) on the progression of head and neck squamous cell carcinoma (HNSCC) is not well known. Methods: From the immunohistochemical analysis of head and neck squamous cell carcinoma (HNSCC) tissues, we divided CAF into two groups depending on the presence or absence of a well-demarcated boundary between epithelial cancer cells and the surrounding extracellular matrix (ECM). Primary culture of CAF was performed, followed by co-transplantation with HNSCC cells into mice oral mucosa, and the tumorigenesis was compared. The mRNA expression patterns between these two CAF groups were compared using DNA microarray analysis. Results: CAFs from cancer tissues that showed no demarcation between ECM and epithelial cancer cells (CAF-Promote) tended to stimulate Matrigel invasion of HNSCC cells. Conversely, CAFs from cancer tissues that showed a boundary with epithelial cancer cells (CAF-Delay) caused no remarkable increase in Matrigel invasion. Compared with CAF-P, CAF-D is less effective in promoting FaDu tumorigenicity in the mouse model. In DNA microarray analysis, COL3A1 and COL6A6 showed particularly high expression in the CAF-D group. Conclusions: These cancer stroma-derived collagen proteins might delay the HNSCC progression. These findings are expected to provide vital information for predicting HNSCC prognosis and developing drug targets in the future.

Download Full-text

Inhibition of F-Box Protein p45SKP2 Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27KIP1 in Vitamin D Analog-Treated Cancer Cells

Endocrinology ◽

10.1210/en.2002-0026 ◽

2003 ◽

Vol 144 (3) ◽

pp. 749-753 ◽

Cited By ~ 40

Author(s):

Roberto Lin ◽

Tian Tian Wang ◽

Wilson H. Miller ◽

John H. White

Keyword(s):

Head And Neck ◽

Cancer Cells ◽

Gene Transcription ◽

Kinase Inhibitor ◽

Cyclin Dependent Kinase ◽

P27kip1 Protein ◽

Protein Levels ◽

Cyclin Dependent Kinase Inhibitor ◽

Squamous Carcinoma Cells ◽

F Box Protein

Treatment of cancer cells with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or its analogs induces growth arrest and expression of the cyclin-dependent kinase inhibitor p27KIP1. Although 1,25(OH)2D3 transiently enhances p27kip1 gene transcription in some cells, its effects on p27KIP1 protein levels are generally more gradual and sustained. This suggests that 1,25(OH)2D3 treatment may be stabilizing p27KIP1 protein, which is sensitive to modification by the SCFSKP2 protein ubiquitin ligase and proteosomal degradation. Here, we show that treatment of AT-84 head and neck squamous carcinoma cells with the 1,25(OH)2D3 analog EB1089 increases p27KIP1 protein levels without significantly affecting expression of its mRNA. EB1089 treatment repressed expression of mRNAs encoding the F-box protein p45SKP2, a marker of poor head and neck cancer prognosis, and the cyclin kinase subunit CKS1, which is essential for targeting p45SKP2 to p27KIP1. This coincided with a reduction of total p45SKP2 protein, and p45SKP2 associated with p27KIP1. Consistent with these findings, turnover of p27KIP1 protein was strongly inhibited in the presence of EB1089. A similar reduction in p45SKP2 expression and stabilization of p27KIP1 protein was observed in 1,25(OH)2D3-sensitive UF-1 promyelocytic leukemia cells, which also respond by transiently increasing p27kip1 gene transcription. Our results reveal that 1,25(OH)2D3 analogs increase levels of p27KIP1 in different cell types by inhibiting expression of SCFSKP2 subunits and reducing turnover of p27KIP1 protein.

Download Full-text

Can Bioelectrical Impedance Analysis and BMI Be a Prognostic Tool in Head and Neck Cancer Patients? A Review of the Evidence

Cancers ◽

10.3390/cancers12030557 ◽

2020 ◽

Vol 12 (3) ◽

pp. 557 ◽

Cited By ~ 1

Author(s):

Maria Mantzorou ◽

Maria Tolia ◽

Antigoni Poultsidi ◽

Eleni Pavlidou ◽

Sousana K. Papadopoulou ◽

...

Keyword(s):

Weight Loss ◽

Head And Neck Cancer ◽

Electrical Properties ◽

Nutritional Status ◽

Head And Neck ◽

Disease Progression ◽

Neck Cancer ◽

Prognostic Role ◽

The Impact

Background: Malnutrition can significantly affect disease progression and patient survival. The efficiency of weight loss and bioimpedance analysis (BIA)-derived measures in the evaluation of malnutrition, and disease progression and prognosis in patients with head and neck cancer (HNC) are an important area of research. Method: The PubMed database was thoroughly searched, using relative keywords in order to identify clinical trials that investigated the role of BIA-derived measures and weight loss on the disease progression and prognosis of patients with HNC. Twenty-seven studies met the criteria. More specifically, six studies examined the prognostic role of the tissue electrical properties in HNC patients; five examined the role of the tissue electrical properties on identifying malnutrition; four studies looked at the changes in the tissue electrical properties of HNC patients; and 12 examined the prognostic role of weight loss on survival and/or treatment outcomes. Results: Several studies have investigated the role of nutritional status tools on prognosis in HNC patients. Current studies investigating the potential of BIA-derived raw data have shown that phase angle (PA) and capacitance of the cell membrane may be considered prognostic factors of survival. Weight loss may be a prognostic factor for treatment toxicity and survival, despite some conflicting evidence. Conclusions: Further studies are recommended to clarify the role of BIA-derived measures on patients’ nutritional status and the impact of PA on clinical outcomes as well as the prognostic role of weight loss.

Download Full-text

The Impact of Antioxidants from the Diet on Breast Cancer Cells Monitored by Raman Microspectroscopy

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180502120804 ◽

2018 ◽

Vol 16 (2) ◽

pp. 127-137

Author(s):

Paula Sofia Coutinho Medeiros ◽

Ana Lúcia Marques Batista de Carvalho ◽

Cristina Ruano ◽

Juan Carlos Otero ◽

Maria Paula Matos Marques

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Line ◽

Breast Cancer Cells ◽

Triple Negative ◽

Breast Adenocarcinoma ◽

Coumaric Acid ◽

Human Breast ◽

The Impact

Background: The impact of the ubiquitous dietary phenolic compound p-coumaric acid on human breast cancer cells was assessed, through a multidisciplinary approach: Combined biological assays for cytotoxicity evaluation and biochemical profiling by Raman microspectroscopic analysis in cells. </P><P> Methods: Para-coumaric acid was shown to exert in vitro chemoprotective and antitumor activities, depending on the concentration and cell line probed: a significant anti-invasive ability was detected for the triple-negative MDA-MB-231 cells, while a high pro-oxidant effect was found for the estrogen- dependent MCF-7 cells. A striking cell selectivity was obtained, with a more noticeable outcome on the triple-negative MDA-MB-231 cell line. Results: The main impact on the cellular biochemical profile was verified to be on proteins and lipids, thus justifying the compound´s anti-invasive effect and chemoprotective ability. Conclusion: p-Coumaric acid was thus shown to be a promising chemoprotective/chemotherapeutic agent, particularly against the low prognosis triple-negative human breast adenocarcinoma.

Download Full-text

Treatment of HIV-associated facial lipoatrophy: impact on infection progression assessed by viral load and CD4 count

Anais Brasileiros de Dermatologia ◽

10.1590/abd1806-4841.2013895 ◽

2013 ◽

Vol 88 (4) ◽

pp. 570-577 ◽

Cited By ~ 5

Author(s):

Flávia Machado Gonçalves Soares ◽

Izelda Maria Carvalho Costa

Keyword(s):

Viral Load ◽

Disease Progression ◽

Statistical Significance ◽

Undetectable Viral Load ◽

Fat Distribution ◽

Cd4 Count ◽

Before And After ◽

Facial Lipoatrophy ◽

A Prospective Study ◽

The Impact

BACKGROUND: HIV/AIDS-Associated Lipodystrophy Syndrome includes changes in body fat distribution, with or without metabolic changes. The loss of fat from the face, called facial lipoatrophy, is one of the most stigmatizing signs of the syndrome.OBJECTIVES:To evaluate the effect of FL treatment using polymethylmethacrylate (PMMA) implants on disease progression, assessed by viral load and CD4 cell count.METHODS: This was a prospective study of 44 patients treated from July 2009 to December 2010. Male and female patients, aged over 18 years, with clinically detectable FL and who had never been treated were included in the study. PMMA implantation was done to fill atrophic areas. Laboratory tests were conducted to measure viral load and CD4 count before and after treatment.RESULTS: Of the 44 patients, 72.72% were male and 27.27% female, mean age of 44.38 years. Before treatment, 82% of patients had undetectable viral load, which increased to 88.6% after treatment, but without statistical significance (p = 0.67). CD4 count before treatment ranged from 209 to 1293, averaging 493.97. After treatment, the average increased to 548.61. The increase in CD4 count after treatment was statistically significant with p = 0.02.CONCLUSION: The treatment of FL with PMMA implants showed a statistically significant increase in CD4 count after treatment, revealing the impact of FL treatment on disease progression. Viral load before and after treatment did not vary significantly.

Download Full-text

Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽

10.3390/cancers13050986 ◽

2021 ◽

Vol 13 (5) ◽

pp. 986

Author(s):

Nada S. Aboelella ◽

Caitlin Brandle ◽

Timothy Kim ◽

Zhi-Chun Ding ◽

Gang Zhou

Keyword(s):

Oxidative Stress ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Redox Homeostasis ◽

Tumor Rejection ◽

Oxygen Species ◽

Antitumor Effects ◽

Key Drivers ◽

Cancer Immunotherapies ◽

The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

Download Full-text

Natural History of NAFLD

Journal of Clinical Medicine ◽

10.3390/jcm10061161 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1161

Author(s):

Raluca Pais ◽

Thomas Maurel

Keyword(s):

Liver Disease ◽

Natural History ◽

Disease Progression ◽

Specific Treatment ◽

Alcoholic Fatty Liver ◽

Individual Level ◽

Close Relationship ◽

History Of ◽

The Individual ◽

The Impact

The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The clinical phenotypes of NAFLD are very heterogeneous in relationship with multiple pathways involved in the disease progression. In the absence of a specific treatment for non-alcoholic steatohepatitis (NASH), it is important to understand the natural history of the disease, to identify and to optimize the control of factors that are involved in disease progression. In this paper we propose a critical analysis of factors that are involved in the progression of the liver damage and the occurrence of extra-hepatic complications (cardiovascular diseases, extra hepatic cancer) in patients with NAFLD. We also briefly discuss the impact of the heterogeneity of the clinical phenotype of NAFLD on the clinical practice globally and at the individual level.

Download Full-text

Diagnosis and treatment delay of head and neck cancers during COVID-19 era in a tertiary care academic hospital: what should we expect?

European Archives of Oto-Rhino-Laryngology ◽

10.1007/s00405-021-06834-1 ◽

2021 ◽

Author(s):

Pietro De Luca ◽

Antonella Bisogno ◽

Vito Colacurcio ◽

Pasquale Marra ◽

Claudia Cassandro ◽

...

Keyword(s):

Retrospective Study ◽

Head And Neck ◽

Retrospective Analysis ◽

Tertiary Care ◽

Diagnostic Delay ◽

Treatment Delay ◽

Head And Neck Cancers ◽

Control Measures ◽

Academic Hospital ◽

The Impact

Abstract Background Since the spreading of SARS-CoV-2 from China, all deferrable medical activities have been suspended, to redirect resources for the management of COVID patients. The goal of this retrospective study was to investigate the impact of COVID-19 on head and neck cancers’ diagnosis in our Academic Hospital. Methods A retrospective analysis of patients treated for head and neck cancers between March 12 and November 1, 2020 was carried out, and we compared these data with the diagnoses of the same periods of the 5 previous years. Results 47 patients were included in this study. We observed a significative reduction in comparison with the same period of the previous 5 years. Conclusions Our findings suggest that the COVID-19 pandemic is associated with a decrease in the number of new H&N cancers diagnoses, and a substantial diagnostic delay can be attributable to COVID-19 control measures.

Download Full-text

Randomized Trial Assessing the Impact of Routine Assessment of Health-Related Quality of Life in Patients with Head and Neck Cancer

Cancers ◽

10.3390/cancers13153826 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3826

Author(s):

Oumar Billa ◽

Franck Bonnetain ◽

Jérôme Chamois ◽

Angeline Ligey ◽

Valérie Ganansia ◽

...

Keyword(s):

Head And Neck ◽

Satisfaction With Care ◽

Related Quality ◽

Eortc Qlq C30 ◽

Health Related ◽

Eortc Qlq ◽

The Impact ◽

Routine Assessment ◽

Eq Vas

The impact of routine assessment of health-related quality of life (HRQoL) on satisfaction with care and the HRQoL of patients with head and neck cancer (HNC) treated with radiotherapy was assessed. Patients with HNC were randomly assigned to two arms, with stratification on sex, cancer localization, and stage of the disease. In the intervention arm, the patients completed the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires first before randomization, then before each medical appointment during radiotherapy (7 weeks), and then every 3 months until 1 year and at 2 years thereafter. In the control arm, the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires were completed before randomization and at 1 year and 2 years thereafter. The primary endpoint was mean change in HRQoL at score at 2 years from baseline assessed by EQ VAS from the EuroQol questionnaire. The secondary endpoint was mean change in satisfaction with care at 2 years from baseline assessed by QLQ-SAT32. Two hundred patients with head and neck cancers were involved in this study (mean age, 58.83 years (range, 36.56–87.89)), of whom 100 were assigned to the intervention arm and 100 to the control arm. Patients in the intervention arm were reported to have a statistically significant increase in EQ VAS at 2 years (p < 0.0001) and exceeded the minimal clinically important difference (mean change at 2 years from baseline = 10.46). In the two arms, mean differences between arms were not statistically significant, but minimal clinically important differences in favor of the intervention arm were found for EQ VAS (mean change difference (MD) = 5.84), satisfaction with care, in particular waiting times (MD = 10.85) and satisfaction with accessibility (MD = 6.52). Routine assessment of HRQoL improves HRQoL and satisfaction with care for patients with HNC treated with radiotherapy.

Download Full-text