Cancers

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Open AccessReview

Technical Considerations for the Generation of Adoptively Transferred T Cells in Cancer Immunotherapy

by Anthony Visioni and Joseph Skitzki

Cancers 2016, 8(9), 86; https://doi.org/10.3390/cancers8090086 - 20 Sep 2016

Cited by 6 | Viewed by 5525

A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, [...] Read more.

A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer. Full article

(This article belongs to the Special Issue Cancer Immunotherapies)

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Open AccessReview

Current Technologies and Recent Developments for Screening of HPV-Associated Cervical and Oropharyngeal Cancers

by Sunny S. Shah, Satyajyoti Senapati, Flora Klacsmann, Daniel L. Miller, Jeff J. Johnson, Hsueh-Chia Chang and M. Sharon Stack

Cancers 2016, 8(9), 85; https://doi.org/10.3390/cancers8090085 - 9 Sep 2016

Cited by 41 | Viewed by 11000

Abstract

Mucosal infection by the human papillomavirus (HPV) is responsible for a growing number of malignancies, predominantly represented by cervical cancer and oropharyngeal squamous cell carcinoma. Because of the prevalence of the virus, persistence of infection, and long latency period, novel and low-cost methods [...] Read more.

Mucosal infection by the human papillomavirus (HPV) is responsible for a growing number of malignancies, predominantly represented by cervical cancer and oropharyngeal squamous cell carcinoma. Because of the prevalence of the virus, persistence of infection, and long latency period, novel and low-cost methods are needed for effective population level screening and monitoring. We review established methods for screening of cervical and oral cancer as well as commercially-available techniques for detection of HPV DNA. We then describe the ongoing development of microfluidic nucleic acid-based biosensors to evaluate circulating host microRNAs that are produced in response to an oncogenic HPV infection. The goal is to develop an ideal screening platform that is low-cost, portable, and easy to use, with appropriate signal stability, sensitivity and specificity. Advances in technologies for sample lysis, pre-treatment and concentration, and multiplexed nucleic acid detection are provided. Continued development of these devices provides opportunities for cancer screening in low resource settings, for point-of-care diagnostics and self-screening, and for monitoring response to vaccination or surgical treatment. Full article

(This article belongs to the Special Issue HPV Associated Cancers)

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Open AccessArticle

Antibiotic Treatment in End-of-Life Cancer Patients—A Retrospective Observational Study at a Palliative Care Center in Sweden

by Maria Helde-Frankling, Jenny Bergqvist, Peter Bergman and Linda Björkhem-Bergman

Cancers 2016, 8(9), 84; https://doi.org/10.3390/cancers8090084 - 6 Sep 2016

Cited by 43 | Viewed by 7292

Abstract

Background: The aim of this study was to elucidate whether palliative cancer patients benefit from antibiotic treatment in the last two weeks of life when an infection is suspected. Method: We reviewed medical records from 160 deceased palliative cancer patients that [...] Read more.

Background: The aim of this study was to elucidate whether palliative cancer patients benefit from antibiotic treatment in the last two weeks of life when an infection is suspected. Method: We reviewed medical records from 160 deceased palliative cancer patients that had been included in previous studies on vitamin D and infections. Patients treated with antibiotics during the last two weeks of life were identified and net effects of treatment (symptom relief) and possible adverse events were extracted from medical records. Results: Seventy-nine patients (49%) had been treated with antibiotics during the last two weeks in life. In 37% (n = 29), the treatment resulted in evident symptom relief and among these 50% had a positive bacterial culture, 43% had a negative culture and in 7% no culture was taken. Among the patients with no or unknown effect of antibiotics, 50% had a positive culture. When the indication for antibiotic treatment was to avoid or treat sepsis, symptom relief was achieved in 50% of the patients (n = 19). Only 4% (n = 3) of the patients experienced adverse events of the treatment (diarrhea, nausea). Conclusions: Treating infections with antibiotics in the last weeks of life may improve the quality of life for palliative cancer patients, especially if sepsis is suspected or confirmed. According to our results, the beneficial effects outweigh the potentially negative outcomes. Full article

(This article belongs to the Special Issue End-of-Life Cancer Care)

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Open AccessReview

Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions

by Rajan Saini, Nathan V. Lee, Kelly Y. P. Liu and Catherine F. Poh

Cancers 2016, 8(9), 83; https://doi.org/10.3390/cancers8090083 - 2 Sep 2016

Cited by 102 | Viewed by 8358

Abstract

Oral cancer is a global health burden with significantly poor survival, especially when the diagnosis is at its late stage. Despite advances in current treatment modalities, there has been minimal improvement in survival rates over the last five decades. The development of local [...] Read more.

Oral cancer is a global health burden with significantly poor survival, especially when the diagnosis is at its late stage. Despite advances in current treatment modalities, there has been minimal improvement in survival rates over the last five decades. The development of local recurrence, regional failure, and the formation of second primary tumors accounts for this poor outcome. For survivors, cosmetic and functional compromises resulting from treatment are often devastating. These statistics underscore the need for novel approaches in the management of this deadly disease. Photodynamic therapy (PDT) is a treatment modality that involves administration of a light-sensitive drug, known as a photosensitizer, followed by light irradiation of an appropriate wavelength that corresponds to an absorbance band of the sensitizer. In the presence of tissue oxygen, cytotoxic free radicals that are produced cause direct tumor cell death, damage to the microvasculature, and induction of inflammatory reactions at the target sites. PDT offers a prospective new approach in controlling this disease at its various stages either as a stand-alone therapy for early lesions or as an adjuvant therapy for advanced cases. In this review, we aim to explore the applications of PDT in oral cancer therapy and to present an overview of the recent advances in PDT that can potentially reposition its utility for oral cancer treatment. Full article

(This article belongs to the Special Issue Photodynamic Cancer Therapy)

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Open AccessReview

Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials

by Benjamin Lu, Brooke A. Green, Jacqueline M. Farr, Flávia C.M. Lopes and Terence J. Van Raay

Cancers 2016, 8(9), 82; https://doi.org/10.3390/cancers8090082 - 1 Sep 2016

Cited by 41 | Viewed by 8000

Abstract

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling [...] Read more.

The Wnt signaling pathway is intricately involved in many aspects of development and is the root cause of an increasing number of diseases. For example, colorectal cancer is the second leading cause of death in the industrialized world and aberration of Wnt signaling within the colonic stem cell is the cause of more than 90% of these cancers. Despite our advances in successfully targeting other pathways, such as Human Epidermal Growth Factor Receptor 2 (HER2), there are no clinically relevant therapies available for Wnt-related diseases. Here, we investigated where research activities are focused with respect to Wnt signaling modulators by searching the United States Patent and Trade Office (USPTO) for patents and patent applications related to Wnt modulators and compared this to clinical trials focusing on Wnt modulation. We found that while the transition of intellectual property surrounding the Wnt ligand-receptor interface to clinical trials is robust, this is not true for specific inhibitors of β-catenin, which is constitutively active in many cancers. Considering the ubiquitous use of the synthetic T-cell Factor/Lymphoid Enhancer Factor (TCF/Lef) reporter system and its success in identifying novel modulators in vitro, we speculate that this model of drug discovery does not capture the complexity of in vivo Wnt signaling that may be required if we are to successfully target the Wnt pathway in the clinic. Notwithstanding, increasingly more complex models are being developed, which may not be high throughput, but more pragmatic in our pursuit to control Wnt signaling. Full article

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Open AccessReview

Imaging in Colorectal Cancer: Progress and Challenges for the Clinicians

by Eric Van Cutsem, Henk M. W. Verheul, Patrik Flamen, Philippe Rougier, Regina Beets-Tan, Rob Glynne-Jones and Thomas Seufferlein

Cancers 2016, 8(9), 81; https://doi.org/10.3390/cancers8090081 - 31 Aug 2016

Cited by 63 | Viewed by 9029

Abstract

The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, [...] Read more.

The use of imaging in colorectal cancer (CRC) has significantly evolved over the last twenty years, establishing important roles in surveillance, diagnosis, staging, treatment selection and follow up. The range of modalities has broadened with the development of novel tracer and contrast agents, and the fusion of technologies such as positron emission tomography (PET) and computed tomography (CT). Traditionally, the most widely used modality for assessing treatment response in metastasised colon and rectal tumours is CT, combined with use of the RECIST guidelines. However, a growing body of evidence suggests that tumour size does not always adequately correlate with clinical outcomes. Magnetic resonance imaging (MRI) is a more versatile technique and dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI may be used to evaluate biological and functional effects of treatment. Integrated fluorodeoxyglucose (FDG)-PET/CT combines metabolic and anatomical imaging to improve sensitivity and specificity of tumour detection, and a number of studies have demonstrated improved diagnostic accuracy of this modality in a variety of tumour types, including CRC. These developments have enabled the progression of treatment strategies in rectal cancer and improved the detection of hepatic metastatic disease, yet are not without their limitations. These include technical, economical and logistical challenges, along with a lack of robust evidence for standardisation and formal guidance. In order to successfully apply these novel imaging techniques and utilise their benefit to provide truly personalised cancer care, advances need to be clinically realised in a routine and robust manner. Full article

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Open AccessReview

Wnt Signaling in Cell Motility and Invasion: Drawing Parallels between Development and Cancer

by Alanna E. Sedgwick and Crislyn D’Souza-Schorey

Cancers 2016, 8(9), 80; https://doi.org/10.3390/cancers8090080 - 29 Aug 2016

Cited by 64 | Viewed by 7596

Abstract

The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss [...] Read more.

The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss recent findings and analogies between Wnt signaling in developmental processes and tumor progression, with a particular focus on cell motility and matrix invasion and highlight the roles of the ARF (ADP-Ribosylation Factor) and Rho-family small GTP-binding proteins. Wnt-regulated signal transduction from cell surface receptors, signaling endosomes and/or extracellular vesicles has the potential to profoundly influence cell movement, matrix degradation and paracrine signaling in both development and disease. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Wnt5a Signaling in Cancer

by Marwa S. Asem, Steven Buechler, Rebecca Burkhalter Wates, Daniel L. Miller and M. Sharon Stack

Cancers 2016, 8(9), 79; https://doi.org/10.3390/cancers8090079 - 26 Aug 2016

Cited by 193 | Viewed by 15523

Abstract

Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition [...] Read more.

Wnt5a is involved in activating several non-canonical WNT signaling pathways, through binding to different members of the Frizzled- and Ror-family receptors. Wnt5a signaling is critical for regulating normal developmental processes, including proliferation, differentiation, migration, adhesion and polarity. However, the aberrant activation or inhibition of Wnt5a signaling is emerging as an important event in cancer progression, exerting both oncogenic and tumor suppressive effects. Recent studies show the involvement of Wnt5a in regulating cancer cell invasion, metastasis, metabolism and inflammation. In this article, we review findings regarding the molecular mechanisms and roles of Wnt5a signaling in various cancer types, and highlight Wnt5a in ovarian cancer. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessReview

Aberrant Wnt Signaling in Leukemia

by Frank J. T. Staal, Farbod Famili, Laura Garcia Perez and Karin Pike-Overzet

Cancers 2016, 8(9), 78; https://doi.org/10.3390/cancers8090078 - 26 Aug 2016

Cited by 68 | Viewed by 8980

Abstract

The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the [...] Read more.

The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment. Full article

(This article belongs to the Special Issue Wnt Signaling in Cancer)

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Open AccessArticle

Reduced Contractility and Motility of Prostatic Cancer-Associated Fibroblasts after Inhibition of Heat Shock Protein 90

by Alex Henke, Omar E. Franco, Grant D. Stewart, Antony C.P. Riddick, Elad Katz, Simon W. Hayward and Axel A. Thomson

Cancers 2016, 8(9), 77; https://doi.org/10.3390/cancers8090077 - 24 Aug 2016

Cited by 17 | Viewed by 6672

Abstract

Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity [...] Read more.

Background: Prostate cancer-associated fibroblasts (CAF) can stimulate malignant progression and invasion of prostatic tumour cells via several mechanisms including those active in extracellular matrix; Methods: We isolated CAF from prostate cancer patients of Gleason Score 6–10 and confirmed their cancer-promoting activity using an in vivo tumour reconstitution assay comprised of CAF and BPH1 cells. We tested the effects of heat shock protein 90 (HSP90) inhibitors upon reconstituted tumour growth in vivo. Additionally, CAF contractility was measured in a 3D collagen contraction assay and migration was measured by scratch assay; Results: HSP90 inhibitors dipalmitoyl-radicicol and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) reduced tumour size and proliferation in CAF/BPH1 reconstituted tumours in vivo. We observed that the most contractile CAF were derived from patients with lower Gleason Score and of younger age compared with the least contractile CAF. HSP90 inhibitors radicicol and 17-DMAG inhibited contractility and reduced the migration of CAF in scratch assays. Intracellular levels of HSP70 and HSP90 were upregulated upon treatment with HSP90 inhibitors. Inhibition of HSP90 also led to a specific increase in transforming growth factor beta 2 (TGFβ2) levels in CAF; Conclusions: We suggest that HSP90 inhibitors act not only upon tumour cells, but also on CAF in the tumour microenvironment. Full article

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

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Cancers, Volume 8, Issue 9 (September 2016) – 10 articles

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