Cancers

Editorial

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3 pages, 191 KiB

Open AccessEditorial

Squamous Cell Carcinoma—A Summary of Novel Advances in Pathogenesis and Therapies

by Imran Khan and Charbel Darido

Cancers 2022, 14(10), 2523; https://doi.org/10.3390/cancers14102523 - 20 May 2022

Cited by 2 | Viewed by 1016

Abstract

Squamous cell carcinomas (SCCs) are cancers of epithelial cells lining the aerodigestive and genitourinary tract [...] Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

2 pages, 147 KiB

Open AccessEditorial

Treatments of Squamous Cell Cancer

by Darido Charbel

Cancers 2020, 12(11), 3229; https://doi.org/10.3390/cancers12113229 - 2 Nov 2020

Viewed by 1230

Abstract

It is now clear that the most common solid cancer is squamous cell cancer (SCC) [...] Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

Research

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22 pages, 7169 KiB

Open AccessArticle

Cathepsin S Evokes PAR₂-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models

by Nguyen Huu Tu, Kenji Inoue, Elyssa Chen, Bethany M. Anderson, Caroline M. Sawicki, Nicole N. Scheff, Hung D. Tran, Dong H. Kim, Robel G. Alemu, Lei Yang, John C. Dolan, Cheng Z. Liu, Malvin N. Janal, Rocco Latorre, Dane D. Jensen, Nigel W. Bunnett, Laura E. Edgington-Mitchell and Brian L. Schmidt

Cancers 2021, 13(18), 4697; https://doi.org/10.3390/cancers13184697 - 19 Sep 2021

Cited by 19 | Viewed by 4336

Abstract

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR₂) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during [...] Read more.

Oral squamous cell carcinoma (SCC) pain is more prevalent and severe than pain generated by any other form of cancer. We previously showed that protease-activated receptor-2 (PAR₂) contributes to oral SCC pain. Cathepsin S is a lysosomal cysteine protease released during injury and disease that can activate PAR₂. We report here a role for cathepsin S in PAR₂-dependent cancer pain. We report that cathepsin S was more active in human oral SCC than matched normal tissue, and in an orthotopic xenograft tongue cancer model than normal tongue. The multiplex immunolocalization of cathepsin S in human oral cancers suggests that carcinoma and macrophages generate cathepsin S in the oral cancer microenvironment. After cheek or paw injection, cathepsin S evoked nociception in wild-type mice but not in mice lacking PAR₂ in Na_v1.8-positive neurons (Par₂Na_v1.8), nor in mice treated with LY3000328 or an endogenous cathepsin S inhibitor (cystatin C). The human oral SCC cell line (HSC-3) with homozygous deletion of the gene for cathepsin S (CTSS) with CRISPR/Cas9 provoked significantly less mechanical allodynia and thermal hyperalgesia, as did those treated with LY3000328, compared to the control cancer mice. Our results indicate that cathepsin S is activated in oral SCC, and that cathepsin S contributes to cancer pain through PAR₂ on neurons. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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17 pages, 2418 KiB

Open AccessArticle

Genomic Signature of Oral Squamous Cell Carcinomas from Non-Smoking Non-Drinking Patients

by Kendrick Koo, Dmitri Mouradov, Christopher M. Angel, Tim A. Iseli, David Wiesenfeld, Michael J. McCullough, Antony W. Burgess and Oliver M. Sieber

Cancers 2021, 13(5), 1029; https://doi.org/10.3390/cancers13051029 - 1 Mar 2021

Cited by 15 | Viewed by 2448

Abstract

Molecular alterations in 176 patients with oral squamous cell carcinomas (OSCC) were evaluated to delineate differences in non-smoking non-drinking (NSND) patients. Somatic mutations and DNA copy number variations (CNVs) in a 68-gene panel and human papilloma virus (HPV) status were interrogated using targeted [...] Read more.

Molecular alterations in 176 patients with oral squamous cell carcinomas (OSCC) were evaluated to delineate differences in non-smoking non-drinking (NSND) patients. Somatic mutations and DNA copy number variations (CNVs) in a 68-gene panel and human papilloma virus (HPV) status were interrogated using targeted next-generation sequencing. In the entire cohort, TP53 (60%) and CDKN2A (24%) were most frequently mutated, and the most common CNVs were EGFR amplifications (9%) and deletions of BRCA2 (5%) and CDKN2A (4%). Significant associations were found for TP53 mutation and nodal disease, lymphovascular invasion and extracapsular spread, CDKN2A mutation or deletion with advanced tumour stage, and EGFR amplification with perineural invasion and extracapsular spread. PIK3CA mutation, CDKN2A deletion, and EGFR amplification were associated with worse survival in univariate analyses (p < 0.05 for all comparisons). There were 59 NSND patients who tended to be female and older than patients who smoke and/or drink, and showed enrichment of CDKN2A mutations, EGFR amplifications, and BRCA2 deletions (p < 0.05 for all comparisons), with a younger subset showing higher mutation burden. HPV was detected in three OSCC patients and not associated with smoking and drinking habits. NSND OSCC exhibits distinct genomic profiles and further exploration to elucidate the molecular aetiology in these patients is warranted. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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Review

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20 pages, 640 KiB

Open AccessReview

Biology and Treatment Advances in Cutaneous Squamous Cell Carcinoma

by Alesha A. Thai, Annette M. Lim, Benjamin J. Solomon and Danny Rischin

Cancers 2021, 13(22), 5645; https://doi.org/10.3390/cancers13225645 - 11 Nov 2021

Cited by 5 | Viewed by 2600

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying [...] Read more.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer diagnosed worldwide. CSCC is generally localized and managed with local therapies such as excision and/or radiotherapy. For patients with unresectable or metastatic disease, recent improvements in our understanding of the underlying biology have led to significant advancements in treatment approaches—including the use of immune checkpoint inhibition (ICI)—which have resulted in substantial gains in response and survival compared to traditional cytotoxic approaches. However, there is a lack of understanding of the biology underpinning CSCC in immunocompromised patients, in whom the risk of developing CSCC is hundreds of times higher compared to immunocompetent patients. Furthermore, current ICI approaches are associated with significant risk of graft rejection in organ transplant recipients who make up a significant proportion of immunocompromised patients. Ongoing scientific and clinical research efforts are needed in order to maintain momentum to increase our understanding and refine our therapeutic approaches for patients with CSCC. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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17 pages, 680 KiB

Open AccessReview

Current Therapeutic Strategies in Patients with Oropharyngeal Squamous Cell Carcinoma: Impact of the Tumor HPV Status

by Alexandre Bozec, Dorian Culié, Gilles Poissonnet, François Demard and Olivier Dassonville

Cancers 2021, 13(21), 5456; https://doi.org/10.3390/cancers13215456 - 29 Oct 2021

Cited by 9 | Viewed by 2297

Abstract

Since there is no published randomized study comparing surgical and non-surgical therapeutic strategies in patients with oropharyngeal squamous cell carcinoma (OPSCC), the therapeutic management of these patients remains highly controversial. While human papillomavirus (HPV)-positive and HPV-negative OPSCC are now recognized as two distinct [...] Read more.

Since there is no published randomized study comparing surgical and non-surgical therapeutic strategies in patients with oropharyngeal squamous cell carcinoma (OPSCC), the therapeutic management of these patients remains highly controversial. While human papillomavirus (HPV)-positive and HPV-negative OPSCC are now recognized as two distinct diseases with different epidemiological, biological, and clinical characteristics, the impact of HPV status on the management of OPSCC patients is still unclear. In this review, we analyze the current therapeutic options in patients with OPSCC, highlighting the most recent advances in surgical and non-surgical therapies, and we discuss the impact of HPV status on the therapeutic strategy. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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25 pages, 1693 KiB

Open AccessReview

Overcoming Resistance to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma

by Natalia García-Sancha, Roberto Corchado-Cobos, Lorena Bellido-Hernández, Concepción Román-Curto, Esther Cardeñoso-Álvarez, Jesús Pérez-Losada, Alberto Orfao and Javier Cañueto

Cancers 2021, 13(20), 5134; https://doi.org/10.3390/cancers13205134 - 13 Oct 2021

Cited by 8 | Viewed by 3591

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of [...] Read more.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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17 pages, 755 KiB

Open AccessReview

The Balance between Differentiation and Terminal Differentiation Maintains Oral Epithelial Homeostasis

by Yuchen Bai, Jarryd Boath, Gabrielle R. White, Uluvitike G. I. U. Kariyawasam, Camile S. Farah and Charbel Darido

Cancers 2021, 13(20), 5123; https://doi.org/10.3390/cancers13205123 - 13 Oct 2021

Cited by 7 | Viewed by 2220

Abstract

The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and [...] Read more.

The oral epithelium is one of the fastest repairing and continuously renewing tissues. Stem cell activation within the basal layer of the oral epithelium fuels the rapid proliferation of multipotent progenitors. Stem cells first undergo asymmetric cell division that requires tightly controlled and orchestrated differentiation networks to maintain the pool of stem cells while producing progenitors fated for differentiation. Rapidly expanding progenitors subsequently commit to advanced differentiation programs towards terminal differentiation, a process that regulates the structural integrity and homeostasis of the oral epithelium. Therefore, the balance between differentiation and terminal differentiation of stem cells and their progeny ensures progenitors commitment to terminal differentiation and prevents epithelial transformation and oral squamous cell carcinoma (OSCC). A recent comprehensive molecular characterization of OSCC revealed that a disruption of terminal differentiation factors is indeed a common OSCC event and is superior to oncogenic activation. Here, we discuss the role of differentiation and terminal differentiation in maintaining oral epithelial homeostasis and define terminal differentiation as a critical tumour suppressive mechanism. We further highlight factors with crucial terminal differentiation functions and detail the underlying consequences of their loss. Switching on terminal differentiation in differentiated progenitors is likely to represent an extremely promising novel avenue that may improve therapeutic interventions against OSCC. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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14 pages, 293 KiB

Open AccessReview

De-Escalation of Therapy for Patients with Early-Stage Squamous Cell Carcinoma of the Anus

by Eric Miller and Jose Bazan

Cancers 2021, 13(9), 2099; https://doi.org/10.3390/cancers13092099 - 27 Apr 2021

Cited by 6 | Viewed by 2062

Abstract

The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with [...] Read more.

The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly in the elderly, with increased mortality in this age group. While the current standard of care for localized SCCA remains chemoradiation (CRT), completion of this treatment can be challenging with risks for severe acute and late toxicity. It remains unclear if full course CRT is required for the management of early-stage SCCA or if de-escalation of treatment is possible without compromising patient outcomes. Alternative therapies include radiation therapy alone or local excision for appropriate patients. Modifying standard CRT may also reduce toxicity including the routine use of intensity-modulated radiation therapy for treatment delivery, modification of treatment volumes, and selection and dosing of concurrent systemic therapy agents. Finally, we provide an overview of currently accruing prospective trials focused on defining the role of de-escalation of therapy in patients with early-stage SCCA. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

Other

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14 pages, 1567 KiB

Open AccessHypothesis

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas

by Linda Kessler, Shivani Malik, Mollie Leoni and Francis Burrows

Cancers 2021, 13(21), 5310; https://doi.org/10.3390/cancers13215310 - 22 Oct 2021

Cited by 3 | Viewed by 2787

Abstract

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis [...] Read more.

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)–specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types. Full article

(This article belongs to the Special Issue Treatments for Squamous Cell Cancer)

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