Cancers

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Open AccessReview

Photodynamic Therapy and Non-Melanoma Skin Cancer

by Liezel L. Griffin and John T. Lear

Cancers 2016, 8(10), 98; https://doi.org/10.3390/cancers8100098 - 22 Oct 2016

Cited by 61 | Viewed by 14483

Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy (PDT) is gaining popularity for the treatment of basal cell carcinoma (BCC), Bowen’s disease (BD) and actinic keratosis (AK). A topical or systemic exogenous photosensitiser, results in selective [...] Read more.

Non-melanoma skin cancer (NMSC) is the most common malignancy among the Caucasian population. Photodynamic therapy (PDT) is gaining popularity for the treatment of basal cell carcinoma (BCC), Bowen’s disease (BD) and actinic keratosis (AK). A topical or systemic exogenous photosensitiser, results in selective uptake by malignant cells. Protoporphyrin IX (PpIX) is produced then activated by the introduction of a light source. Daylight-mediated MAL (methyl aminolaevulinate) PDT for AKs has the advantage of decreased pain and better patient tolerance. PDT is an effective treatment for superficial BCC, BD and both individual and field treatment of AKs. Excellent cosmesis can be achieved with high patient satisfaction. Variable results have been reported for nodular BCC, with improved outcomes following pretreatment and repeated PDT cycles. The more aggressive basisquamous, morphoeic infiltrating subtypes of BCC and invasive squamous cell carcinoma (SCC) are not suitable for PDT. Prevention of “field cancerization” in organ transplant recipients on long-term immunosuppression and patients with Gorlin syndrome (naevoid basal cell carcinoma syndrome) is a promising development. The optimisation of PDT techniques with improved photosensitiser delivery to target tissues, new generation photosensitisers and novel light sources may expand the future role of PDT in NMSC management. Full article

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

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Open AccessReview

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

by Magdalena Paolino and Josef M. Penninger

Cancers 2016, 8(10), 97; https://doi.org/10.3390/cancers8100097 - 21 Oct 2016

Cited by 92 | Viewed by 13281

Abstract

The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as [...] Read more.

The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy. Full article

(This article belongs to the Special Issue TAM family receptors in cancer biology and therapeutic resistance)

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Open AccessReview

Modulation of the Anti-Tumor Efficacy of Photodynamic Therapy by Nitric Oxide

by Albert W. Girotti

Cancers 2016, 8(10), 96; https://doi.org/10.3390/cancers8100096 - 20 Oct 2016

Cited by 23 | Viewed by 5612

Abstract

Nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes is a free radical molecule involved in a wide variety of normophysiologic and pathophysiologic processes. Included in the latter category are cancer promotion, progression, and resistance to therapeutic intervention. Animal tumor photodynamic therapy [...] Read more.

Nitric oxide (NO) produced by nitric oxide synthase (NOS) enzymes is a free radical molecule involved in a wide variety of normophysiologic and pathophysiologic processes. Included in the latter category are cancer promotion, progression, and resistance to therapeutic intervention. Animal tumor photodynamic therapy (PDT) studies several years ago revealed that endogenous NO can reduce PDT efficacy and that NOS inhibitors can alleviate this. Until relatively recently, little else was known about this anti-PDT effect of NO, including: (a) the underlying mechanisms; (b) type(s) of NOS involved; and (c) whether active NO was generated in vascular cells, tumor cells, or both. In addressing these questions for various cancer cell lines exposed to PDT-like conditions, the author’s group has made several novel findings, including: (i) exogenous NO can scavenge lipid-derived free radicals arising from photostress, thereby protecting cells from membrane-damaging chain peroxidation; (ii) cancer cells can upregulate inducible NOS (iNOS) after a PDT-like challenge and the resulting NO can signal for resistance to photokilling; (iii) photostress-surviving cells with elevated iNOS/NO proliferate and migrate/invade more aggressively; and (iv) NO produced by photostress-targeted cells can induce greater aggressiveness in non-targeted bystander cells. In this article, the author briefly discusses these various means by which NO can interfere with PDT and how this may be mitigated by use of NOS inhibitors as PDT adjuvants. Full article

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

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Open AccessReview

Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites

by Vjekoslav Tomaić

Cancers 2016, 8(10), 95; https://doi.org/10.3390/cancers8100095 - 19 Oct 2016

Cited by 158 | Viewed by 15783

Abstract

Approximately 200 human papillomaviruses (HPVs) infect human epithelial cells, of which the alpha and beta types have been the most extensively studied. Alpha HPV types mainly infect mucosal epithelia and a small group of these causes over 600,000 cancers per year worldwide at [...] Read more.

Approximately 200 human papillomaviruses (HPVs) infect human epithelial cells, of which the alpha and beta types have been the most extensively studied. Alpha HPV types mainly infect mucosal epithelia and a small group of these causes over 600,000 cancers per year worldwide at various anatomical sites, especially anogenital and head-and-neck cancers. Of these the most important is cervical cancer, which is the leading cause of cancer-related death in women in many parts of the world. Beta HPV types infect cutaneous epithelia and may contribute towards the initiation of non-melanoma skin cancers. HPVs encode two oncoproteins, E6 and E7, which are directly responsible for the development of HPV-induced carcinogenesis. They do this cooperatively by targeting diverse cellular pathways involved in the regulation of cell cycle control, of apoptosis and of cell polarity control networks. In this review, the biological consequences of papillomavirus targeting of various cellular substrates at diverse anatomical sites in the development of HPV-induced malignancies are highlighted. Full article

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

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Open AccessArticle

Mreg Activity in Tumor Response to Photodynamic Therapy and Photodynamic Therapy-Generated Cancer Vaccines

by Mladen Korbelik, Judith Banáth and Wei Zhang

Cancers 2016, 8(10), 94; https://doi.org/10.3390/cancers8100094 - 15 Oct 2016

Cited by 18 | Viewed by 5164

Abstract

Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction [...] Read more.

Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction is closely dependent on the associated antitumor immune response. The present study investigated whether the immunodepletion of granulocytic Mregs in host mice by anti-GR1 antibody would improve the response of tumors to PDT or PDT vaccines in these animals. Anti-GR1 administration immediately after Temoporfin-PDT of mouse SCCVII tumors abrogated curative effect of PDT. The opposite effect, increasing PDT-mediated tumor cure-rates was attained by delaying anti-GR1 treatment to 1 h post PDT. With PDT vaccines, multiple anti-GR1 administrations (days 0, 4, and 8 post vaccination) improved the therapy response with SCCVII tumors. The results with PDT suggest that neutrophils (boosting antitumor effect of this therapy) that are engaged immediately after photodynamic light treatment are within one hour replaced with a different myeloid population, presumably Mregs that hampers the therapy-mediated antitumor effect. Anti-GR1 antibody, when used with optimal timing, can improve the efficacy of both PDT of tumors in situ and PDT-generated cancer vaccines. Full article

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

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Open AccessReview

Hypericin in the Dark: Foe or Ally in Photodynamic Therapy?

by Veronika Huntosova and Katarina Stroffekova

Cancers 2016, 8(10), 93; https://doi.org/10.3390/cancers8100093 - 14 Oct 2016

Cited by 22 | Viewed by 5437

Abstract

Photosensitizers (PSs) in photodynamic therapy (PDT) are, in most cases, administered systemically with preferential accumulation in malignant tissues; however, exposure of non-malignant tissues to PS may also be clinically relevant, when PS molecules affect the pro-apoptotic cascade without illumination. Hypericin (Hyp) as PS [...] Read more.

Photosensitizers (PSs) in photodynamic therapy (PDT) are, in most cases, administered systemically with preferential accumulation in malignant tissues; however, exposure of non-malignant tissues to PS may also be clinically relevant, when PS molecules affect the pro-apoptotic cascade without illumination. Hypericin (Hyp) as PS and its derivatives have long been studied, regarding their photodynamic and photocytotoxic characteristics. Hyp and its derivatives have displayed light-activated antiproliferative and cytotoxic effects in many tumor cell lines without cytotoxicity in the dark. However, light-independent effects of Hyp have emerged. Contrary to the acclaimed Hyp minimal dark cytotoxicity and preferential accumulation in tumor cells, it was recently been shown that non-malignant and malignant cells uptake Hyp at a similar level. In addition, Hyp has displayed light-independent toxicity and anti-proliferative effects in a wide range of concentrations. There are multiple mechanisms underlying Hyp light-independent effects, and we are still missing many details about them. In this paper, we focus on Hyp light-independent effects at several sub-cellular levels—protein distribution and synthesis, organelle ultrastructure and function, and Hyp light-independent effects regarding reactive oxygen species (ROS). We summarize work from our laboratories and that of others to reveal an intricate network of the Hyp light-independent effects. We propose a schematic model of pro- and anti-apoptotic protein dynamics between cell organelles due to Hyp presence without illumination. Based on our model, Hyp can be explored as an adjuvant therapeutic drug in combination with chemo- or radiation cancer therapy. Full article

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

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Open AccessReview

Antioxidant Activity during Tumor Progression: A Necessity for the Survival of Cancer Cells?

by Mark A. Hawk, Chelsea McCallister and Zachary T. Schafer

Cancers 2016, 8(10), 92; https://doi.org/10.3390/cancers8100092 - 13 Oct 2016

Cited by 56 | Viewed by 6682

Abstract

Antioxidant defenses encompass a variety of distinct compounds and enzymes that are linked together through their capacity to neutralize and scavenge reactive oxygen species (ROS). While the relationship between ROS and tumorigenesis is clearly complex and context dependent, a number of recent studies [...] Read more.

Antioxidant defenses encompass a variety of distinct compounds and enzymes that are linked together through their capacity to neutralize and scavenge reactive oxygen species (ROS). While the relationship between ROS and tumorigenesis is clearly complex and context dependent, a number of recent studies have suggested that neutralizing ROS can facilitate tumor progression and metastasis in multiple cancer types through distinct mechanisms. These studies therefore infer that antioxidant activity may be necessary to support the viability and/or the invasive capacity of cancer cells during tumor progression and metastasis. Here, we discuss some of the accumulating evidence suggesting a role for antioxidant activity in facilitating tumor progression. Full article

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

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Open AccessReview

Boosting Tumor-Specific Immunity Using PDT

by Nicole Maeding, Thomas Verwanger and Barbara Krammer

Cancers 2016, 8(10), 91; https://doi.org/10.3390/cancers8100091 - 6 Oct 2016

Cited by 76 | Viewed by 6211

Abstract

Photodynamic therapy (PDT) is a cancer treatment with a long-standing history. It employs the application of nontoxic components, namely a light-sensitive photosensitizer and visible light, to generate reactive oxygen species (ROS). These ROS lead to tumor cell destruction, which is accompanied by the [...] Read more.

Photodynamic therapy (PDT) is a cancer treatment with a long-standing history. It employs the application of nontoxic components, namely a light-sensitive photosensitizer and visible light, to generate reactive oxygen species (ROS). These ROS lead to tumor cell destruction, which is accompanied by the induction of an acute inflammatory response. This inflammatory process sends a danger signal to the innate immune system, which results in activation of specific cell types and release of additional inflammatory mediators. Activation of the innate immune response is necessary for subsequent induction of the adaptive arm of the immune system. This includes the priming of tumor-specific cytotoxic T lymphocytes (CTL) that have the capability to directly recognize and kill cells which display an altered self. The past decades have brought increasing appreciation for the importance of the generation of an adaptive immune response for long-term tumor control and induction of immune memory to combat recurrent disease. This has led to considerable effort to elucidate the immune effects PDT treatment elicits. In this review we deal with the progress which has been made during the past 20 years in uncovering the role of PDT in the induction of the tumor-specific immune response, with special emphasis on adaptive immunity. Full article

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

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Open AccessReview

Photodynamic Therapy for Non-Melanoma Skin Cancers

by Diana K. Cohen and Peter K. Lee

Cancers 2016, 8(10), 90; https://doi.org/10.3390/cancers8100090 - 4 Oct 2016

Cited by 99 | Viewed by 7095

Abstract

Non‐melanoma skin cancer (NMSC) is traditionally treated with surgical excision. Nonsurgical methods such as cryotherapy and topical chemotherapeutics, amongst other treatments, are other options. Actinic keratosis (AKs) are considered precancerous lesions that eventually may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) [...] Read more.

Non‐melanoma skin cancer (NMSC) is traditionally treated with surgical excision. Nonsurgical methods such as cryotherapy and topical chemotherapeutics, amongst other treatments, are other options. Actinic keratosis (AKs) are considered precancerous lesions that eventually may progress to squamous cell carcinoma (SCC). Photodynamic therapy (PDT) offers an effective treatment for AKs, and is also effective for superficial basal cell carcinoma (BCC). Nodular BCC and Bowen’s disease (SCC in situ) have shown acceptable response rates with PDT, although recurrence rates are higher for these two NMSC subtypes. Methylaminolevulinate (MAL) PDT is a more effective treatment option than 5‐aminolevulinic acid (ALA) PDT for nodular BCC. Several studies have shown that PDT results in superior cosmetic outcomes compared to surgical treatment. PDT is overall well‐tolerated, with pain being the most common side effect. Full article

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

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Open AccessArticle

Translating into Practice Cancer Patients’ Views on Do-Not-Resuscitate Decision-Making

by Ian N. Olver and Jaklin A. Eliott

Cancers 2016, 8(10), 89; https://doi.org/10.3390/cancers8100089 - 27 Sep 2016

Cited by 4 | Viewed by 4757

Abstract

Do-not-resuscitate (DNR) orders are necessary if resuscitation, the default option in hospitals, should be avoided because a patient is known to be dying and attempted resuscitation would be inappropriate. To avoid inappropriate resuscitation at night, if no DNR order has been recorded, after-hours [...] Read more.

Do-not-resuscitate (DNR) orders are necessary if resuscitation, the default option in hospitals, should be avoided because a patient is known to be dying and attempted resuscitation would be inappropriate. To avoid inappropriate resuscitation at night, if no DNR order has been recorded, after-hours medical staff are often asked to have a DNR discussion with patients whose condition is deteriorating, but with whom they are unfamiliar. Participants in two qualitative studies of cancer patients’ views on how to present DNR discussions recognized that such patients are at different stages of understanding of their situation and may not be ready for a DNR discussion; therefore, a one-policy-fits-all approach was thought to be inappropriate. To formulate a policy that incorporates the patient’s views, we propose that a standard form which mandates a DNR discussion is replaced by a “blank sheet” with instructions to record the progress of the discussion with the patient, and a medical recommendation for a DNR decision to guide the nursing staff in case of a cardiac arrest. Such an advance care directive would have to honor specifically expressed patient or guardian wishes whilst allowing for flexibility, yet would direct nurses or other staff so that they can avoid inappropriate cardiopulmonary resuscitation of a patient dying of cancer. Full article

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

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Open AccessReview

Photodynamic Therapy in Gynecologic Malignancies: A Review of the Roswell Park Cancer Institute Experience

by Paul C. Mayor and Shashikant Lele

Cancers 2016, 8(10), 88; https://doi.org/10.3390/cancers8100088 - 23 Sep 2016

Cited by 15 | Viewed by 4591

Abstract

Photodynamic therapy (PDT) is a treatment modality used in the management of solid tumor malignancies that employs the use of a photosensitizing agent, a light source and oxygen in order to illicit a direct cytotoxic effect. Its use in gynecologic malignancies is somewhat [...] Read more.

Photodynamic therapy (PDT) is a treatment modality used in the management of solid tumor malignancies that employs the use of a photosensitizing agent, a light source and oxygen in order to illicit a direct cytotoxic effect. Its use in gynecologic malignancies is somewhat novel and has been used for palliative and curative intent. At the Roswell Park Cancer Institute, the use of PDT in the management of gynecologic cancers began in the mid 1980s and since that time 35 patients have received PDT as a treatment for recurrent or metastatic cutaneous and vulvar, vaginal, anal, and cervical recurrences. In our experience, 85% patients with metastatic cutaneous lesions had a complete response. Twenty-seven percent of patients with metastatic vaginal, cervical or anal recurrences had a complete response to therapy with a median response time of 28 months. Side effects from the treatment included moderate to severe burning sensation, pain and edema at the treatment site requiring narcotic pain medication for symptom management in patients who underwent treatment to cutaneous lesions as well as lower genital tract recurrences. PDT should be considered an option in patients who are too frail to undergo the standard of care or decline the standard of care in lieu of a less invasive treatment modality. Full article

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

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Open AccessReview

Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma

by Darrin V. Bann, Daniel G. Deschler and Neerav Goyal

Cancers 2016, 8(10), 87; https://doi.org/10.3390/cancers8100087 - 22 Sep 2016

Cited by 23 | Viewed by 7167

Abstract

The immune system plays a key role in preventing tumor formation by recognizing and destroying malignant cells. For over a century, researchers have attempted to harness the immune response as a cancer treatment, although this approach has only recently achieved clinical success. Head [...] Read more.

The immune system plays a key role in preventing tumor formation by recognizing and destroying malignant cells. For over a century, researchers have attempted to harness the immune response as a cancer treatment, although this approach has only recently achieved clinical success. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with cigarette smoking, alcohol consumption, betel nut use, and human papillomavirus infection. Unfortunately, worldwide mortality from HNSCC remains high, partially due to limits on therapy secondary to the significant morbidity associated with current treatments. Therefore, immunotherapeutic approaches to HNSCC treatment are attractive for their potential to reduce morbidity while improving survival. However, the application of immunotherapies to this disease has been challenging because HNSCC is profoundly immunosuppressive, resulting in decreased absolute lymphocyte counts, impaired natural killer cell function, reduced antigen-presenting cell function, and a tumor-permissive cytokine profile. Despite these challenges, numerous clinical trials testing the safety and efficacy of immunotherapeutic approaches to HNSCC treatment are currently underway, many of which have produced promising results. This review will summarize immunotherapeutic approaches to HNSCC that are currently undergoing clinical trials. Full article

(This article belongs to the Special Issue Cancer Immunotherapies)

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