Special Issue:
Challenges and Opportunities in Skin Cancer
C DeGiovanni
Department of Dermatology, University Hospitals Sussex NHS Foundation Trust. Brighton General Hospital, Elm Grove, Brighton, BN2 3EW. United Kingdom
M Patel
Department of Dermatology, University Hospitals Sussex NHS Foundation Trust. Brighton General Hospital, Elm Grove, Brighton, BN2 3EW. United Kingdom
P Drake
Department of Dermatology, University Hospitals Sussex NHS Foundation Trust. Brighton General Hospital, Elm Grove, Brighton, BN2 3EW. United Kingdom
P Sains
SainsSurgical. 4 Elsworthy, Thames Ditton, Surrey, KT7 0YP
V Sridhar
Osney thermo-fluids Laboratory, Department of Engineering Science, University of Oxford. Oxford. OX1 3PJ
Kam Chana
Osney thermo-fluids Laboratory, Department of Engineering Science, University of Oxford. Oxford. OX1 3PJ
Abstract
Skin cancer is one of the most common cancers in the world. Skin cancer is currently a global public health problem that is escalating. In the UK, the incidence of malignant melanoma has increased from 837 per year to 6963 per year in males and 1609 per year to 6952 per year in females between 1981 and 2018. Early diagnosis and treatment, as with any other disease will have a positive outcome in terms of survival and costs of management. Advances in technology have allowed the development of tools that provide rapid and sensitive diagnosis of many diseases. This paper describes the development and use of a thermal based technique which directly measures the thermal properties of skin. The Thermal Product Sensor (TPS), a new biosensor, has been demonstrated in the diagnosis of skin malignancies. The technique is quantitative and is shown to distinguish between normal and malignant skin. The study demonstrates on 12 patients the thermal product technique successfully detected skin cancers in comparison to normal skin.
Hamza Malick, BS
Texas A&M College of Medicine, Dallas, Texas
Seo Won Cho, BS
Texas A&M College of Medicine, Dallas, Texas
Kyle C. Lauck, MD
Baylor University Medical Center, Dallas, Texas
Aaisha Firdaus, MBBS
Katihar Medical College & Hospital, Katihar, Bihar, India
Dario Kivelevitch
Texas A&M College of Medicine, Dallas, Texas; Baylor University Medical Center, Dallas, Texas
Abstract
Psoriasis, a chronic immune-mediated skin disorder impacting millions globally, is increasingly recognized for its links to various disease processes. As our understanding of immune dysregulation in psoriasis progresses, acknowledging the pivotal role of dysregulated T-cells in the pathogenic development of the persistent inflammatory state becomes crucial. This immune dysregulation and the resulting prevalent inflammatory state have raised concerns about psoriasis potentially serving as a significant comorbidity in cancer development among patients. To contribute to this discussion, we conducted a global retrospective cohort study with propensity score matching (PSM) using the TriNetX Analytics platform. The study aimed to investigate whether patients diagnosed with psoriasis face an elevated risk in the development of cutaneous malignancies, encompassing both melanoma and non-melanoma skin cancers. Our findings confirmed a noteworthy concern, revealing a significantly increased risk of developing cutaneous neoplasms in individuals with psoriasis. In conclusion, our study underscores the importance of heightened awareness and the necessity for routine skin cancer screenings in this unique patient population. The observed association between psoriasis and an increased risk of cutaneous neoplasms highlights the need for proactive medical interventions and emphasizes the potential impact of psoriasis as a comorbidity in the context of cancer development.
Chase Paulson
University of Utah School of Medicine, School of Medicine, Salt Lake City, UT
D James Barker
University of Utah School of Medicine, School of Medicine, Salt Lake City, UT
Christian Pompoco
Moran Eye Center, Salt Lake City, UT
Sam Taylor
University of Utah School of Medicine, School of Medicine, Salt Lake City, UT
Matthew Conley
University of Utah School of Medicine, School of Medicine, Salt Lake City, UT
Ayesha Patil
Moran Eye Center, Salt Lake City, UT
Nnana Amakiri
Moran Eye Center, Salt Lake City, UT
Brian Stagg
Moran Eye Center, Salt Lake City, UT
Robert Ritch
Einhorn Clinical Research, Department of New York Eye and Ear Infirmary of Mount Sinai, New York, New York
Jae H Kang
Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, MA
Janey L Wiggs
Mass Eye and Ear, Boston, MA
Karen Curtin
University of Utah School of Medicine, School of Medicine, Salt Lake City, UT; Moran Eye Center, Salt Lake City, UT
Barbara Wirostko
Moran Eye Center, Salt Lake City, UT
Abstract
Background: Prior data suggest an association between non-melanoma skin cancer, i.e., basal and squamous cell cancers most often located in areas of sun exposure, and pseudoexfoliation syndrome. This study aimed to evaluate the association between these conditions and UV exposure through a detailed questionnaire in a large and robust Utah population.
Methods: The two arms of this study are a population-based study (evaluated via chart review) and a UV exposure study (evaluated via a questionnaire). Participants answered a questionnaire designed to assess lifelong UV exposure, including leisure and occupational sun exposure, likelihood to tan or burn in early life, eye and hair color, smoking behavior, vitamin D deficiency, skin cancer history, alcohol consumption, and caffeine intake.
Conclusion: Descriptive findings suggest UV exposure over an adult’s lifespan may associate with a higher risk of non-melanoma skin cancer in Utah exfoliation patients vs. unaffected individuals. Patients with exfoliation glaucoma reside at higher elevations than non-glaucoma patients.
Yunfeng Zhao
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Annapoorna Sreedhar
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Chunjing Zhang
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA; School of Basic Medicine, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China
Noel Jacquet
Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
Abstract
Upregulation of uncoupling protein 2 (UCP2) is considered a prosurvival mechanism for cancer cells. This prosurvival function is thought to be mediated by UCP2’s uncoupling activity which reduces the production of superoxide in the mitochondria. However, exactly how highly expressed UCP2 regulates cell proliferation, cell cycle, and cell death during the early stage of tumorigenesis has not been studied thoroughly. For this purpose, we generated UCP2 stably overexpressed JB6 Cl-41 cells (a skin cell transformation model) and performed studies to answer the above questions. Our results demonstrated that UCP2 overexpression enhanced cell proliferation, activation of the oncoprotein Fra-1, anchorage-independent growth, 3D spheroids growth, and glucose uptake during skin cell transformation. Next, our results demonstrated that UCP2 overexpression resulted in marked decreases in the proportion of the cells in the G1 phase and an increase of cells in the S phase of the cell cycle, which was accompanied by increased expression of Cyclin E and Cdk2. Lastly, UCP2 overexpression did not enhance or suppress apoptosis during skin cell transformation, as indicated by Annexin V and active caspase 3/7 staining. Taken together, these data suggest that UCP2 upregulation mainly enhances the Fra-1 oncogenic pathway which drives cell proliferation, without inhibiting apoptosis during skin cell transformation.
David John Mackay Smith
University of Queensland
Abstract
Approximately 10% of genes oscillate according to a circadian clock. Even though cells are capable of independent oscillation there is a master controller in the brain, the suprachiasmatic nucleus (SCN), that provides a coordinated response throughout the body, influenced by daily and seasonal patterns of light and heat. These genes have widely varied functions but are significantly influential in DNA damage repair, the cell cycle, cellular proliferation and apoptosis, as well as metabolic function. Normal circadian rhythms are essential for the body’s natural defence against disease and cancer. Deregulation may enhance the capacity for carcinogenesis in the skin and the influence of the circadian clock helps explain two of the anomalies of melanoma exposure patterns: A higher incidence amongst indoor as opposed to outdoor workers and on intermittently as opposed chronically exposed skin.
Paul J. Davis, M.D.
Department of Medicine, Albany Medical College, Albany, NY USA; NanoPharmaceuticals LLC, Troy, NY USA.
Aleck Hercbergs
Department of Radiation Oncology, The Cleveland Clinic, Cleveland, OH USA.
Hung-Yun Lin
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Matthew Leinung
Department of Medicine, Albany Medical College, Albany, NY USA; 2NanoPharmaceuticals LLC, Troy, NY USA.
Shaker A. Mousa
NanoPharmaceuticals LLC, Troy, NY USA; Vascular Vision Company, Troy, NY.
Abstract
Thyroid hormone as L-thyroxine (T4) at physiological concentrations acts at its cell surface receptor on integrin avb3 to stimulate cancer cell proliferation1. These proliferation studies have been conducted in vitro, but pharmacological reduction of T4 and substitution of nuclear receptor ligand 3,3’,5-triiodo-L-thyronine (T3) is a state of euthyroid hypothyroxinemia that has been shown clinically to arrest tumor growth in patients with cancer. T3 is inactive at physiological levels at the plasma membrane integrin receptor. A preclinical study of human basal cell carcinoma (BCC) cells has shown that the integrin thyroid hormone receptor regulates BCC radiosensitivity. While the large majority of BCCs are very manageable clinically, a small number of such tumors are aggressive. In this review of documented and proposed effects of T4 on BCC cells, we raise the possibility that BCC aggressiveness reflects T4 actions on its thyrointegrin target. The functions affected by T4 at the integrin in other human cancers include enhanced cell proliferation, anti-apoptosis, immune checkpoint regulation and metastasis, as well as state of radiosensitivity. The importance of investigating this possible pathophysiology is that euthyroid hypothyroxinemia may be tested as a treatment option.
The Skin Cancer Paradox
Joseph C. DiNardo
MS Toxicologist
Abstract
Although the safety and efficacy of ultraviolet filters (sunscreens) is widely accepted by consumers and medical professionals, the scientific community has yet to validate this conclusion. This is evident based on multiple literature searches obtained from PubMed, Google Scholar, ScienceDirect, ResearchGate, sunscreen manufacturers and dermatologic organization websites. In the absences of definitive data, industry continues to promote the use of these products to prevent cancers, specifically a 40% reduction in squamous cell carcinoma and a 50% reduction in melanoma based on one confounded non-reproduced study with numerous design flaws. This causes consumers to be misinformed leading them to intentionally increase ultraviolet light exposure, increasing their risk of skin cancers. Until the scientific community can clearly demonstrate that these products reduce/eliminate skin cancers, consumers should follow sun avoidance measures.
David John Mackay Smith
University of Queensland, St Lucia QLD 4072, Australia
Abstract
Public health messages clearly state the risks of solar radiation and how the risk can be mitigated. This is supported by the availability of creams that effectively block out the ultraviolet component of solar radiation. Why then does the incidence of skin cancer and particularly melanoma remain so disturbingly high in Caucasian populations?
Almost all organisms on the planet have had to adapt to the presence of solar radiation since the beginning of evolutionary time. There are beneficial effects as well as risks in exposure, not the least of which is that it is the ultimate energy source for living species.
We need to re-examine attitudes and exposure patterns with an appreciation that some exposure is essential for good health. A balance needs to be found between benefits and risks. This can only be done by understanding that there are a range of wavelengths of light with different effects rather than a focus solely on the adverse effects of the ultraviolet component.
Norman A. Brooks, M.D.
Institution: Skin Cancer Medical Center
Abstract
The majority of physicians treating melanoma in situ recommend a 5mm to 1cm margin with excision into the subcutaneous tissue extending between the superficial and the deep fat. There is always the potential for an unrecognized invasive component in a melanoma in situ, making aqueous zinc chloride solution an ideal agent to treat the excision wound of a melanoma in situ of the trunk and extremities. Zinc chloride solution penetrates deeply and widely, killing and fixing tissue when applied to the excision wound, facilitating the excision by allowing for a simple saucerized excision with a narrower and thinner margin while ensuring the treatment of any possible unrecognized invasive components. Zinc chloride has been used in a paste since 1835 to treat skin cancers and melanoma but unlike pastes zinc chloride in solution is recognized by the U.S. Food & Drug Administration as a generally safe substance (Code of Federal Regulations Title 21 [Part 182]). The solution penetrates as deeply and widely and effectively as in the paste which Mohs described to be an inactive vehicle for the active ingredient, zinc chloride solution. Mohs reported a large significant survival benefit (p=0.003) for invasive melanoma using surgery combined with zinc chloride over conventional melanoma surgery. Zinc chloride solution without the paste is a new medicine effective as a surgical adjuvant in the treatment of the excision wound of a melanoma in situ of the trunk and extremities. Zinc chloride can be used as a surgical adjuvant for any melanoma, but melanoma in situ of the trunk and extremities is the logical starting point for a physician interested in using this adjuvant in the treatment of melanoma. Zinc chloride is very powerful and potentially scarring and should be used on the excision wound of a previously histologically diagnosed melanoma only.
David John Mackay Smith
University of Queensland, Brisbane, Australia.
Abstract
The keratinocyte and the melanocyte, the main cellular constituents of the epidermis, are two very different cell types. Despite their different origins and functionality, they come together in the skin, synergistically, to function as a unit to control the adverse effects of solar exposure. The most significant element in this protective process is the ability of the melanocyte to produce melanin. This pigmented polymer is responsible for constitutive skin colour that plays a part in our identity as human individuals but more importantly, provides a tanning response. A change in pigmentation that provides both an immediate and prolonged protective effect from the damaging components of solar radiation.
The melanocortin 1 receptor, a cell surface receptor on the melanocyte, receives paracrine stimulation in the form of hormonal communication from the keratinocyte, initiating a series of intracellular molecular interactions in the melanocyte, eventually involving transcription factors in the nucleus, most notably the microphthalmia-associated transcription factor, resulting in upregulation of enzymatic production of melanin and finally, its transfer back to the keratinocyte.
The melanocortin 1 receptor is highly polymorphic and unfortunately this results in the Caucasians’ having constitutionally fairer skin combined with an incomplete tanning response, resulting in a higher susceptibility to skin cancer.
The melanocyte is a relatively long-lived cell and over its extended life span can accumulate a series of mutational events. With malignant transition to melanoma this oncogenic baggage, when combined with antiapoptotic machinery that helps melanocyte survival, resulting in relatively rapid progression of the malignant process and contributing to its resistance to therapeutics.
Natasha Boyette
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ
Ava Dalton
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ
Yearam Tak
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ
Sophie Kang
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ
Subbu Apparsundaram
Cellix Biosciences, Inc., Newark, New Jersey; Cellix Bio Private Limited, Hyderabad, India
Mahesh Kandula
Cellix Biosciences, Inc., Newark, New Jersey; Cellix Bio Private Limited, Hyderabad, India
John York
Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ; Institute for the Global Entrepreneur at the Rady School of Management and the Jacobs School of Engineering, University of California, San Diego, CA
Abstract
Introduction: Capecitabine is an oral prodrug of 5-FU, which interpatient pharmacokinetic (PK) variability related to liver function and severe adverse events (e.g., hand-foot syndrome, myelosuppression, and neurotoxicity) limits. CLX-155 is a novel oral 5’-DFCR prodrug involving 5’-DFCR as an intermediate for generating 5-FU, unlike capecitabine, which the liver does not metabolize. This study addresses the following research question: what is the activity of CLX-155 in a human colon cancer xenograft model in nude mice?
Methods: This study involved 50 Foxn1 athymic nude female mice implanted with the human colon cancer cell line HCT116 (5 million cells per site). Investigators randomized animals into five treatment groups (N = 10): vehicle control, CLX-155 at doses of 125, 250, and 500 mg/kg/day, or capecitabine 1000 mg/kg/day. Animals received oral treatment once daily for five days a week with two days off for a total of three consecutive weeks. Investigators evaluated treatment toxicity based on body weight loss. Calculations for tumor growth inhibition involved comparing changes in tumor volume on a given day to tumor volumes on Day 1.
Results: CLX-155 demonstrated statistically significant, dose-dependent tumor growth inhibition at all doses compared to vehicle control (p<0.0001). Tumor growth inhibition at Day 15 for CLX-155 treatment groups of 125, 250, and 500 mg/kg/day was 57.8%, 70.4%, and 90.6% respectively. Two animals in the CLX-155 500 mg/kg/day treatment group experienced complete tumor regression, and all animals in the CLX-155 treatment groups survived. Two animals in the CLX-155 250 and 500 mg/kg/day dosing groups experienced a decrease in body weight. In contrast, two mice in the capecitabine group exhibited clinical signs of hunchback and scaly skin, progressive weight loss, and eventual death.
Conclusion: CLX-155 demonstrated comparable tumor growth inhibition to capecitabine but at a lower dose, suggesting increased potency. In addition, CLX-155 exhibited improved tolerability and fewer adverse effects. These promising results support further investigation in Phase 1 clinical trials for managing colon cancer.
Haruo Sugiyama
Department of Cancer Immunology, Osaka University Graduate School of Medicine.
Abstract
Wilms’ tumor gene 1 (WT1) overexpresses in almost all kinds of hematological malignancies and solid tumors (hereinafter referred to as cancer). Therefore, WT1 protein is a ubiquitous tumor-associated antigen (TAA). Many clinical studies of WT1-targeted cancer immunotherapies (hereinafter referred to as WT1 cancer vaccine), including WT1 peptide vaccine, WT1 peptide-pulsed dendritic cell (WT1-DC) vaccine, and WT1 mRNA-electroporated dendritic cell (WT1 mRNA-DC) vaccine had been conducted for the treatment of almost all kinds of cancer. The clinical effect was promising, whereas the major side effects were the temporary fever and skin reaction on the vaccine injection sites and not significant. The appropriate combination therapy of WT1 cancer vaccine and chemotherapy enhanced WT1 immune response against cancer. Gemcitabine (GEM), for example, increased WT1 immune response through the promotion of the expression of WT1 antigen protein and HLA class I/II molecules in cancer. Furthermore, WT1 cancer vaccine immediately after hematopoietic stem cell transplantation (HSCT) induced sufficient WT1 immune response regardless of severe immunocompromised conditions and exerted sufficient clinical effect, suggesting that the immune condition immediately after HSCT should be suitable for the priming of WT1 immune response. Moreover, the combination therapy of WT1 cancer vaccine and immune checkpoint inhibitors (ICIs) was promising. Compared to the other TAAs, WT1 is especially unique in that it expresses not only in cancer cells but also in their stem cells at the quiescent state of cell-cycle, which are resistant to chemo-and radio-therapies. This uniqueness of WT1 largely contributes to cure cancer through the complete eradication of WT1-expressing cancer stem cells by WT1 immune response against them. Since the complete eradication of cancer stem cells is essential to cure cancer, and since only immune cells against cancer are considered to be able to kill the cancer stem cells at the quiescent state of cell-cycle, the introduction of immunotherapy, especially of WT1 cancer vaccine with sufficient safety is essential in the cure-oriented treatments of cancer. Accumulated clinical results suggest that WT1 cancer vaccine should be useful for cancer prevention, and the development of WT1 cancer prevention vaccine is awaited.
