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Article ; Online: HPV-associated oropharyngeal cancer: in search of surrogate biomarkers for early lesions.

Lim, Yvonne X / D'Silva, Nisha J

2024 Volume 43, Issue 8, Page(s) 543–554

Abstract: The incidence of oropharyngeal cancer (OPSCC) has escalated in the past few decades; this has largely been triggered by high-risk human papillomavirus (HPV). Early cancer screening is needed for timely clinical intervention and may reduce mortality and ... ...

Abstract	The incidence of oropharyngeal cancer (OPSCC) has escalated in the past few decades; this has largely been triggered by high-risk human papillomavirus (HPV). Early cancer screening is needed for timely clinical intervention and may reduce mortality and morbidity, but the lack of knowledge about premalignant lesions for OPSCC poses a significant challenge to early detection. Biomarkers that identify individuals at high risk for OPSCC may act as surrogate markers for precancer but these are limited as only a few studies decipher the multistep progression from HPV infection to OPSCC development. Here, we summarize the current literature describing the multistep progression from oral HPV infection, persistence, and tumor development in the oropharynx. We also examine key challenges that hinder the identification of premalignant lesions in the oropharynx and discuss potential biomarkers for oropharyngeal precancer. Finally, we evaluate novel strategies to improve investigations of the biological process that drives oral HPV persistence and OPSCC, highlighting new developments in the establishment of a genetic progression model for HPV + OPSCC and in vivo models that mimic HPV + OPSCC pathogenesis.
MeSH term(s)	Humans ; Papillomavirus Infections/complications ; Carcinoma, Squamous Cell ; Papillomaviridae/genetics ; Oropharyngeal Neoplasms/genetics ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-01-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-023-02927-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Cytokines secreted by inflamed oral mucosa: implications for oral cancer progression.

Danella, Erika B / Costa de Medeiros, Marcell / D'Silva, Nisha J

Oncogene

2023 Volume 42, Issue 15, Page(s) 1159–1165

Abstract: The oral mucosa has an essential role in protecting against physical, microbial, and chemical harm. Compromise of this barrier triggers a wound healing response. Key events in this response such as immune infiltration, re-epithelialization, and stroma ... ...

Abstract	The oral mucosa has an essential role in protecting against physical, microbial, and chemical harm. Compromise of this barrier triggers a wound healing response. Key events in this response such as immune infiltration, re-epithelialization, and stroma remodeling are coordinated by cytokines that promote cellular migration, invasion, and proliferation. Cytokine-mediated cellular invasion and migration are also essential features in cancer dissemination. Therefore, exploration of cytokines that regulate each stage of oral wound healing will provide insights about cytokines that are exploited by oral squamous cell carcinoma (SCC) to promote tumor development and progression. This will aid in identifying potential therapeutic targets to constrain SCC recurrence and increase patient survival. In this review, we discuss cytokines that overlap in oral wounds and SCC, emphasizing how these cytokines promote cancer progression.
MeSH term(s)	Cytokines/metabolism ; Disease Progression ; Mouth Neoplasms/metabolism ; Mouth Mucosa/metabolism ; Wound Healing ; Carcinoma, Squamous Cell/metabolism ; Humans
Chemical Substances	Cytokines
Language	English
Publishing date	2023-03-06
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-023-02649-y
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Article ; Online: Clinical, morphologic and molecular heterogeneity of HPV-associated oropharyngeal cancer.

Lim, Yvonne X / Mierzwa, Michelle L / Sartor, Maureen A / D'Silva, Nisha J

Oncogene

2023 Volume 42, Issue 40, Page(s) 2939–2955

Abstract: The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC ... ...

Abstract	The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC respond very favorably to standard aggressive treatment, the emphasis has changed to reducing treatment intensity. However, recent multi-center clinical trials failed to show non-inferiority of de-escalation strategies on a population basis, highlighting the need to select low-risk patients likely to respond to de-intensified treatments. In contrast, there is a substantial proportion of patients who develop recurrent disease despite aggressive therapy. This supports that HPV + OPSCC is not a homogeneous disease, but comprises distinct subtypes with clinical and biological variations. The overall goal for this review is to identify biomarkers for HPV + OPSCC that may be relevant for patient stratification for personalized treatment. We discuss HPV + OPSCC as a heterogeneous disease from multifaceted perspectives including clinical behavior, tumor morphology, and molecular phenotype. Molecular profiling from bulk tumors as well as single-cell sequencing data are discussed as potential driving factors of heterogeneity between tumor subgroups. Finally, we evaluate key challenges that may impede in-depth investigations of HPV + OPSCC heterogeneity and outline potential future directions, including a section on racial and ethnic differences.
MeSH term(s)	Humans ; Carcinoma, Squamous Cell/pathology ; Papillomavirus Infections/complications ; Papillomavirus Infections/genetics ; Oropharyngeal Neoplasms/genetics ; Oropharyngeal Neoplasms/pathology ; Squamous Cell Carcinoma of Head and Neck ; Head and Neck Neoplasms ; Papillomaviridae/genetics
Language	English
Publishing date	2023-09-04
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-023-02819-y
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Article ; Online: The 3D's of Neural Phenotypes in Oral Cancer: Distance, Diameter, and Density.

D'Silva, Nisha J / Perez-Pacheco, Cindy / Schmitd, Ligia B

Advanced biology

2022 Volume 7, Issue 2, Page(s) e2200188

Abstract: Squamous cell carcinoma of the oral cavity (OSCC) is the most common type of head and neck cancer; survival is poor, and response to treatment varies. Metastasis or recurrence in the regional lymph nodes is associated with poor survival. Consequently, ... ...

Abstract	Squamous cell carcinoma of the oral cavity (OSCC) is the most common type of head and neck cancer; survival is poor, and response to treatment varies. Metastasis or recurrence in the regional lymph nodes is associated with poor survival. Consequently, overt or occult spread to the lymph nodes is used to identify patients who will receive adjuvant radiation therapy. Perineural invasion and the diameter of nerves exhibiting perineural invasion have also been suggested to be of prognostic significance. The explosion of interest in cancer neuroscience in the last two decades has led to novel biological insights into interactions between nerves and tumor cells. However, the criteria for defining perineural invasion have lagged behind current knowledge. It is important to re-evaluate the concept of perineural invasion and identify other neural phenotypes in OSCC that can impact treatment selection and prognosis. In addition to perineural invasion, neural phenotypes that are of potential relevance to tumor progression include nerve-tumor distance, nerve diameter, and nerve density. This manuscript discusses the translational significance of recent mechanistic studies on the progression of oral cancer.
MeSH term(s)	Humans ; Neoplasm Invasiveness ; Mouth Neoplasms ; Prognosis ; Head and Neck Neoplasms ; Lymph Nodes/pathology
Language	English
Publishing date	2022-11-14
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ISSN	2701-0198
ISSN (online)	2701-0198
DOI	10.1002/adbi.202200188
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Article: Cancer-associated keratinocytes: new members of the microenvironment in head and neck cancer.

Danella, Erika B / Costa De Medeiros, Marcell / D'Silva, Nisha J

Molecular & cellular oncology

2021 Volume 8, Issue 4, Page(s) 1933329

Abstract: The tumor microenvironment is a complex ecosystem of malignant and nonmalignant cells and extracellular proteins that work together to enhance tumor progression. We identified a mechanism in which adjacent nonmalignant epithelium enhances invasion of ... ...

Abstract	The tumor microenvironment is a complex ecosystem of malignant and nonmalignant cells and extracellular proteins that work together to enhance tumor progression. We identified a mechanism in which adjacent nonmalignant epithelium enhances invasion of squamous cell carcinoma, thereby expanding the tumor microenvironment to include cancer-associated keratinocytes.
Language	English
Publishing date	2021-07-01
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2021.1933329
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Article ; Online: Nerve density in cancer: Less is better.

Schmitd, Ligia B / Perez-Pacheco, Cindy / D'Silva, Nisha J

FASEB bioAdvances

2021 Volume 3, Issue 10, Page(s) 773–786

Abstract: The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, ... ...

Abstract	The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, usually only a few nerves inside a tumor are affected by perineural invasion, while most nerves are not. Mechanistic studies have shown nerve-secreted factors promote tumor growth and invasion thereby making tumors more aggressive. Therefore, the overall number of nerves in the tumor microenvironment should be more representative of the nerve-tumor biological interaction than perineural invasion. This review summarizes the available clinical information about nerve density as a measure of clinical outcome in cancer and explores the mechanisms underlying nerve density in cancer, specifically, neurogenesis, axonogenesis, and neurotropism.
Language	English
Publishing date	2021-07-11
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2573-9832
ISSN (online)	2573-9832
DOI	10.1096/fba.2021-00046
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Article ; Online: Nerve density in cancer

Ligia B. Schmitd / Cindy Perez‐Pacheco / Nisha J. D'Silva

FASEB BioAdvances, Vol 3, Iss 10, Pp 773-

Less is better

2021 Volume 786

Abstract: Abstract The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. ... ...

Abstract	Abstract The density of nerves in cancer is emerging as a relevant clinical parameter for patient survival. Nerves in the tumor microenvironment have been associated with poor survival and recurrence, particularly if involved in perineural invasion. However, usually only a few nerves inside a tumor are affected by perineural invasion, while most nerves are not. Mechanistic studies have shown nerve‐secreted factors promote tumor growth and invasion thereby making tumors more aggressive. Therefore, the overall number of nerves in the tumor microenvironment should be more representative of the nerve‐tumor biological interaction than perineural invasion. This review summarizes the available clinical information about nerve density as a measure of clinical outcome in cancer and explores the mechanisms underlying nerve density in cancer, specifically, neurogenesis, axonogenesis, and neurotropism.
Keywords	neoplasms ; nerve tissue/pathology ; review ; tumor microenvironment ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune-relevant aspects of murine models of head and neck cancer.

Rossa, Carlos / D'Silva, Nisha J

Oncogene

2019 Volume 38, Issue 21, Page(s) 3973–3988

Abstract: Head and neck cancers (HNCs) cause significant mortality and morbidity. There have been few advances in therapeutic management of HNC in the past 4 to 5 decades, which support the need for studies focusing on HNC biology. In recent years, increased ... ...

Abstract	Head and neck cancers (HNCs) cause significant mortality and morbidity. There have been few advances in therapeutic management of HNC in the past 4 to 5 decades, which support the need for studies focusing on HNC biology. In recent years, increased recognition of the relevance of the host response in cancer progression has led to novel therapeutic strategies and putative biomarkers of tumor aggressiveness. However, tumor-immune interactions are highly complex and vary with cancer type. Pre-clinical, in vivo models represent an important and necessary step in understanding biological processes involved in development, progression and treatment of HNC. Rodents (mice, rats, hamsters) are the most frequently used animal models in HNC research. The relevance and utility of information generated by studies in murine models is unquestionable, but it is also limited in application to tumor-immune interactions. In this review, we present information regarding the immune-specific characteristics of the murine models most commonly used in HNC research, including immunocompromised and immunocompetent animals. The particular characteristics of xenograft, chemically induced, syngeneic, transgenic, and humanized models are discussed in order to provide context and insight for researchers interested in the in vivo study of tumor-immune interactions in HNC.
MeSH term(s)	Animals ; Disease Models, Animal ; Head and Neck Neoplasms/immunology ; Heterografts/immunology ; Humans ; Immunocompromised Host/immunology ; Mice
Language	English
Publishing date	2019-01-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-019-0686-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Non-murine models to investigate tumor-immune interactions in head and neck cancer.

Rossa, Carlos / D'Silva, Nisha J

Oncogene

2019 Volume 38, Issue 25, Page(s) 4902–4914

Abstract: The immune response has important roles in the biology of solid tumors, including oncogenesis, tumor growth, invasion and metastasis, and response to treatment. Improved understanding of tumor-immune system interactions has provided promising therapeutic ...

Abstract	The immune response has important roles in the biology of solid tumors, including oncogenesis, tumor growth, invasion and metastasis, and response to treatment. Improved understanding of tumor-immune system interactions has provided promising therapeutic options that are based on the rescue and enhancement of the anti-tumoral host response. Immune-based treatments have been approved for clinical use in various types of cancer, including head and neck cancer (HNC); other strategies involving combination therapies are currently in development. These novel therapies were developed based on knowledge derived from in vitro, in silico, and in vivo pre-clinical studies. However, clinical trials seldom replicate the efficacy observed in pre-clinical animal studies. This lack of correlation between pre-clinical studies and clinical trials may be related to limitations of the models used; which highlights the relevance of considering immune-related aspects of different pre-clinical models. Murine models are the most frequently used pre-clinical models of HNC and are discussed elsewhere. Non-murine models have characteristics that offer unique opportunities for the study of HNC etiology, therapeutic strategies, and tumor-immune system interactions. The current review focuses on immune-related aspects of non-murine models, including dog, cat, pig, zebrafish, and frog, that could be used to investigate tumor-immune interactions in HNC.
MeSH term(s)	Animals ; Anura ; Cats ; Cell Communication/immunology ; Disease Models, Animal ; Dogs ; Head and Neck Neoplasms/immunology ; Head and Neck Neoplasms/pathology ; Immunity, Innate/physiology ; Mice ; Swine ; Tumor Escape/physiology ; Tumor Microenvironment/immunology ; Zebrafish
Language	English
Publishing date	2019-03-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-019-0776-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Radiation resistance in head and neck squamous cell carcinoma: dire need for an appropriate sensitizer.

Hutchinson, Marsha-Kay N D / Mierzwa, Michelle / D'Silva, Nisha J

Oncogene

2020 Volume 39, Issue 18, Page(s) 3638–3649

Abstract: Radiation is a significant treatment for patients with head and neck cancer. Despite advances to improve treatment, many tumors acquire radiation resistance resulting in poor survival. Radiation kills cancer cells by inducing DNA double-strand breaks. ... ...

Abstract	Radiation is a significant treatment for patients with head and neck cancer. Despite advances to improve treatment, many tumors acquire radiation resistance resulting in poor survival. Radiation kills cancer cells by inducing DNA double-strand breaks. Therefore, radiation resistance is enhanced by efficient repair of damaged DNA. Head and neck cancers overexpress EGFR and have a high frequency of p53 mutations, both of which enhance DNA repair. This review discusses the clinical criteria for radiation resistance in patients with head and neck cancer and summarizes how cancer cells evade radiation-mediated apoptosis by p53- and epidermal growth factor receptor (EGFR)-mediated DNA repair. In addition, we explore the role of cancer stem cells in promoting radiation resistance, and how the abscopal effect provides rationale for combination strategies with immunotherapy.
MeSH term(s)	Apoptosis/radiation effects ; Cell Proliferation/radiation effects ; DNA Breaks, Double-Stranded/radiation effects ; DNA Damage/radiation effects ; DNA Repair/radiation effects ; ErbB Receptors/genetics ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; Radiation Tolerance/genetics ; Squamous Cell Carcinoma of Head and Neck/genetics ; Squamous Cell Carcinoma of Head and Neck/pathology ; Squamous Cell Carcinoma of Head and Neck/radiotherapy ; Tumor Suppressor Protein p53/genetics
Chemical Substances	TP53 protein, human ; Tumor Suppressor Protein p53 ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2020-03-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-020-1250-3
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