IL-6 in the Ecosystem of Head and Neck Cancer: Possible Therapeutic Perspectives.

Interleukin-6 (IL-6) is a highly potent cytokine involved in multiple biological processes. It was previously reported to play a distinct role in inflammation, autoimmune and psychiatric disorders, ageing and various types of cancer. Furthermore, it is understood that IL-6 and its signaling pathways are substantial players in orchestrating the cancer microenvironment. Thus, they appear to be potential targets in anti-tumor therapy. The aim of this article is to elucidate the role of IL-6 in the tumor ecosystem and to review the possible therapeutic approaches in head and neck cancer.

The Abscopal Effect in the Era of Checkpoint Inhibitors.

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.

Melanoma xenotransplant on the chicken chorioallantoic membrane: a complex biological model for the study of cancer cell behaviour.

The globally increasing incidence of cancer, including melanoma, requires novel therapeutic strategies. Development of successful novel drugs is based on clear identification of the target mechanisms responsible for the disease progression. The specific cancer microenvironment represents a critically important aspect of cancer biology, which cannot be properly studied in simplistic cell culture conditions. Among other traditional options, the study of melanoma cell growth on the chicken chorioallantoic membrane offers several significant advantages. This model offers increased complexity compared to usual in silico culture models and still remains financially affordable. Using this model, we studied the growth of three established human melanoma cell lines: A2058, BLM, G361. The combination of histology, immunohistochemistry with the application of human-specific antibodies, intravascular injection of contrast material such as filtered Indian ink, Mercox solution and phosphotungstic acid, and X-ray micro-CT and live-cell monitoring was employed. Melanoma cells spread well on the chicken chorioallantoic membrane. However, invasion into the stroma of the chorioallantoic membrane and the limb primordium graft was rare. The melanoma cells also significantly influenced the architecture of the blood vessel network, resulting in the orientation of the vessels to the site of the tumour cell inoculation. The system of melanoma cell culture on the chorioallantoic membrane is suitable for the study of melanoma cell growth, particularly of rearrangement of the host vascular pattern after cancer cell implantation. The system also has promising potential for further development.

Fibroblasts potentiate melanoma cells in vitro invasiveness induced by UV-irradiated keratinocytes.

Melanoma represents a malignant disease with steadily increasing incidence. UV-irradiation is a recognized key factor in melanoma initiation. Therefore, the efficient prevention of UV tissue damage bears a critical potential for melanoma prevention. In this study, we tested the effect of UV irradiation of normal keratinocytes and their consequent interaction with normal and cancer-associated fibroblasts isolated from melanoma, respectively. Using this model of UV influenced microenvironment, we measured melanoma cell migration in 3-D collagen gels. These interactions were studied using DNA microarray technology, immunofluorescence staining, single cell electrophoresis assay, viability (dead/life) cell detection methods, and migration analysis. We observed that three 10 mJ/cm2 fractions at equal intervals over 72 h applied on keratinocytes lead to a 50% increase (p < 0.05) in in vitro invasion of melanoma cells. The introduction cancer-associated fibroblasts to such model further significantly stimulated melanoma cells in vitro invasiveness to a higher extent than normal fibroblasts. A panel of candidate gene products responsible for facilitation of melanoma cells invasion was defined with emphasis on IL-6, IL-8, and CXCL-1. In conclusion, this study demonstrates a synergistic effect between cancer microenvironment and UV irradiation in melanoma invasiveness under in vitro condition.

Plasma miR-155, miR-203, and miR-205 are Biomarkers for Monitoring of Primary Cutaneous T-Cell Lymphomas.

Primary cutaneous T-cell lymphomas (CTCL) affect the skin and tend to transform and spread. CTCL involves primarily the Mycosis fungoides (MF) and more aggressive Sezary syndrome (SS). Oncogenic microRNAs (miRs) are stable epigenetic inhibitors often deregulated in the tumour and detectable as biomarkers in non-cellular fractions of peripheral blood. The tumour-specific expression of miR-155, miR-203, and miR-205 was shown to correctly diagnose CTCL. We herein asked whether these microRNAs can be used as plasma biomarkers for clinical CTCL monitoring. Patients with CTCL (n = 10) and controls with non-malignant conditions (n = 11) repeatedly donated plasma samples every ca. five months. MicroRNAs were detected in the plasma samples by specifically-primed RT-PCR followed by multivariate analyses of the miR expression dynamics. We herein established the plasma miR-classifier for detecting CTCL based on the miR-155 upregulation and miR-203/miR-205 downregulation with 100% specificity and 94% sensitivity. The 3-miR-score in the consecutive samples coincided with the clinical outcome of MF and SS patients such as the therapy response or changes in the clinical stage or tumor size. Quantitation of the selected microRNAs in plasma is a specific and straightforward approach for evaluating CTCL outcome representing, thus, a valuable tool for CTCL diagnostics and therapy response monitoring.

Simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness.

Tumour microenvironment plays a critical role in cell invasion and metastasis. To investigate the role of cancer-associated fibroblasts (CAFs) in melanoma cell invasiveness, we used 3D spheroid invasion assay. The effect of conditioned media from normal fibroblasts and CAFs cultivated alone or co-cultivated with melanoma cells on BLM or A2058 melanoma spheroid invasion was analysed. We found that conditioned media from CAFs and CAFs co-cultured with melanoma cells, especially, promote invasion and migration, without significant effect on melanoma cell proliferation. We further analysed the expression of pro-invasive cytokines IL-8 and IL-6 in media and found that melanoma cells are dominant producers of IL-8 and fibroblasts are dominant producers of IL-6 in 2D monocultures, while co-cultivation of CAFs with melanoma cells induces production/secretion of IL-6 and IL-8 into the media. The analyses of IL-6 levels in 3D cultures and human melanoma samples, however, revealed that at least in some cases IL-6 is also produced directly by melanoma cells. Analysis of the role of IL-6 and IL-8 in CAF-induced melanoma invasion, using neutralising antibodies, revealed that simultaneous blocking of IL-6 and IL-8 is sufficient to fully inhibit CAF-induced human melanoma cell invasiveness. In summary, these experiments indicate the important role of CAFs and IL-8 and IL-6 cytokines in melanoma cell invasiveness.

Melanoma cells influence the differentiation pattern of human epidermal keratinocytes.

BACKGROUND: Nodular melanoma is one of the most life threatening tumors with still poor therapeutic outcome. Similarly to other tumors, permissive microenvironment is essential for melanoma progression. Features of this microenvironment are arising from molecular crosstalk between the melanoma cells (MC) and the surrounding cell populations in the context of skin tissue. Here, we study the effect of melanoma cells on human primary keratinocytes (HPK). Presence of MC is as an important modulator of the tumor microenvironment and we compare it to the effect of nonmalignant lowly differentiated cells also originating from neural crest (NCSC). METHODS: Comparative morphometrical and immunohistochemical analysis of epidermis surrounding nodular melanoma (n = 100) was performed. Data were compared to results of transcriptome profiling of in vitro models, in which HPK were co-cultured with MC, normal human melanocytes, and NCSC, respectively. Differentially expressed candidate genes were verified by RT-qPCR. Biological activity of candidate proteins was assessed on cultured HPK. RESULTS: Epidermis surrounding nodular melanoma exhibits hyperplastic features in 90% of cases. This hyperplastic region exhibits aberrant suprabasal expression of keratin 14 accompanied by loss of keratin 10. We observe that MC and NCSC are able to increase expression of keratins 8, 14, 19, and vimentin in the co-cultured HPK. This in vitro finding partially correlates with pseudoepitheliomatous hyperplasia observed in melanoma biopsies. We provide evidence of FGF-2, CXCL-1, IL-8, and VEGF-A participation in the activity of melanoma cells on keratinocytes. CONCLUSION: We conclude that the MC are able to influence locally the differentiation pattern of keratinocytes in vivo as well as in vitro. This interaction further highlights the role of intercellular interactions in melanoma. The reciprocal role of activated keratinocytes on biology of melanoma cells shall be verified in the future.

Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease.

OBJECTIVES: IL-35 is a member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. IL-35 exerts immunomodulatory activities in experimental and human autoimmune inflammatory conditions. Our aim was to assess IL-35 expression in the skin and circulation of SSc patients and to characterize its potential association with SSc-related features. METHODS: Expression of IL-35 in skin and dermal fibroblasts was quantified by quantitative PCR, immunohistochemistry and immunofluorescence. Serum levels of IL-35 (by ELISA), CRP (by turbidimetry), ANA (by immunofluorescence) and autoantibodies of the ENA complex (by immunoblot) were measured in 40 SSc patients. Serum IL-35 was determined in 40 age- and sex-matched healthy controls. RESULTS: IL-35 expression was increased in SSc skin and dermal fibroblasts in a TGF-ß-dependent manner. IL-35 induced an activated phenotype in resting fibroblasts and enhanced the release of collagen. IL-35 serum levels were increased in patients with SSc compared with healthy controls [median 83.9 (interquartile range 45.1-146.1) vs 36.2 (interquartile range 17.2-49.4) pg/ml, P < 0.0001]. Serum IL-35 was negatively correlated with disease duration (r = -0.4339, P = 0.0052). In line with this finding, serum IL-35 was increased in patients with an early SSc pattern on capillaroscopy assessment compared with those with active and late SSc patterns. CONCLUSION: The present study demonstrates overexpression of IL-35 in SSc skin, dermal fibroblasts and serum. TGF-ß induces IL-35, which in turn activates resting fibroblasts and enhances the release of collagen, thereby contributing to aberrant TGF-ß signalling in SSc. Increased serum IL-35 is associated with early, inflammatory stages of SSc.

Revelation of fibroblast protein commonalities and differences and their possible roles in wound healing and tumourigenesis using co-culture models of cells.

BACKGROUND INFORMATION: The in vitro co-culture models of communication between normal fibroblasts and epithelial cells, such as keratinocytes or squamous cell carcinoma cells of FaDu line representing wound healing or cancer development, were established by non-direct contact between the cells and utilised in this study to examine epithelia-induced changes in overall fibroblast proteome patterns. RESULTS: We were able to select the proteins co-regulated in both models in order to evaluate possible molecular commonalities between wound healing and tumour development. Amongst the most pronounced were the proteins implemented in contractile activity and formation of actin cytoskeleton such as caldesmon, calponin-2, myosin regulatory light-chain 12A and cofilin-1, which were expressed independently of the presence of α-smooth muscle actin. Additionally, proteins altered differently highlighted functional and cellular phenotypes during transition of fibroblasts towards myofibroblasts or cancer-associated fibroblasts. Results showed coordinated regulation of cytoskeleton proteins selective for wound healing which were lost in tumourigenesis model. Vimentin bridged this group of proteins with other regulated proteins in human fibroblasts involved in protein or RNA processing and metabolic regulation. CONCLUSIONS: The findings provide strong support for crucial role of stromal microenvironment in wound healing and tumourigenesis. In particular, epithelia-induced protein changes in fibroblasts offer new potential targets which may lead to novel tailored cancer therapeutic strategies.

Cancer Microenvironment: What Can We Learn from the Stem Cell Niche.

Epidermal stem cells (ESCs) are crucial for maintenance and self- renewal of skin epithelium and also for regular hair cycling. Their role in wound healing is also indispensable. ESCs reside in a defined outer root sheath portion of hair follicle-also known as the bulge region. ECS are also found between basal cells of the interfollicular epidermis or mucous membranes. The non-epithelial elements such as mesenchymal stem cell-like elements of dermis or surrounding adipose tissue can also contribute to this niche formation. Cancer stem cells (CSCs) participate in formation of common epithelial malignant diseases such as basal cell or squamous cell carcinoma. In this review article, we focus on the role of cancer microenvironment with emphasis on the effect of cancer-associated fibroblasts (CAFs). This model reflects various biological aspects of interaction between cancer cell and CAFs with multiple parallels to interaction of normal epidermal stem cells and their niche. The complexity of intercellular interactions within tumor stroma is depicted on example of malignant melanoma, where keratinocytes also contribute the microenvironmental landscape during early phase of tumor progression. Interactions seen in normal bulge region can therefore be an important source of information for proper understanding to melanoma. The therapeutic consequences of targeting of microenvironment in anticancer therapy and for improved wound healing are included to article.

Synthetic polyamine BPA-C8 inhibits TGF-ß1-mediated conversion of human dermal fibroblast to myofibroblasts and establishment of galectin-1-rich extracellular matrix in vitro.

Cancer-associated fibroblasts (CAFs) play a role in the progression of malignant tumors. They are formed by conversion of fibroblasts to smooth muscle α-actin-positive (SMA-positive) myofibroblasts. Polyamines are known to change the arrangement of the actin cytoskeleton by binding to the anionic actin. We tested the effect of the synthetic polyamine BPA-C8 on the transition of human dermal fibroblasts to myofibroblasts induced either by TGF-ß1 alone or by TGF-ß1 together with adhesion/growth-regulatory galectin-1. Pre-existing CAFs, myofibroblasts from pancreatitis, and rat smooth muscle cells were also exposed to BPA-C8. BPA-C8 impaired myofibroblast formation from activated fibroblasts, but it had no effect on cells already expressing SMA. BPA-C8 also reduced the occurrence of an extracellular matrix around the activated fibroblasts. The reported data thus extend current insights into polyamine activity, adding interference with tumor progression to the tumor-promoting processes warranting study.

Cultivation-dependent plasticity of melanoma phenotype.

Malignant melanoma is a highly aggressive tumor with increasing incidence and high mortality. The importance of immunohistochemistry in diagnosis of the primary tumor and in early identification of metastases in lymphatic nodes is enormous; however melanoma phenotype is frequently variable and thus several markers must be employed simultaneously. The purposes of this study are to describe changes of phenotype of malignant melanoma in vitro and in vivo and to investigate whether changes of environmental factors mimicking natural conditions affect the phenotype of melanoma cells and can revert the typical in vitro loss of diagnostic markers. The influence of microenvironment was studied by means of immunocytochemistry on co-cultures of melanoma cells with melanoma-associated fibroblast and/or in conditioned media. The markers typical for melanoma (HMB45, Melan-A, Tyrosinase) were lost in malignant cells isolated from malignant effusion; however, tumor metastases shared identical phenotype with primary tumor (all markers positive). The melanoma cell lines also exerted reduced phenotype in vitro. The only constantly present diagnostic marker observed in our experiment was S100 protein and, in lesser extent, also Nestin. The phenotype loss was reverted under the influence of melanoma-associated fibroblast and/or both types of conditioned media. Loss of some markers of melanoma cell phenotype is not only of diagnostic significance, but it can presumably also contribute to biological behavior of melanoma. The presented study shows how the conditions of cultivation of melanoma cells can influence their phenotype. This observation can have some impact on considerations about the role of microenvironment in tumor biology.

Loss of adhesion/growth-regulatory galectin-9 from squamous cell epithelium in head and neck carcinomas.

Galectins are potent effectors of cell adhesion and growth regulation. Their expression as comples network necessitates systematic study of each member of this family. Toward this aim, we here focus on the tandem-repeat-type galectin-9. Its presence is monitored in normal squamous epithelium of the head and neck, the surgical margin, and four types of squamous cell carcinoma. Lectin presence was detected in cells of the basal layer of the epithelium. All galectin-9-negative epithelia showed aberrant positivity for keratins 14 and 19. The surgical margin presented either a normal pattern of galectin-9 and keratin presence or a mosaic-like presence/absence of galectin-9 and aberrant expression of both keratins 14 and 19. All studied specimens of squamous cell carcinoma were negative for galectin-9. When biotinylated galectin-9, or its N-terminal domain, was tested, no significant tissue reactivity for both probes was observed. Neuraminidase treatment generated reactivity to the N-domain. In conclusion, galectin-9 is expressed in the majority of samples of normal epithelium, along with regular presence of keratins 14 or 19. This lectin can represent a potential marker of normality in the cases of the studied squamous cell epithelia.

Retrospective Analysis of 118 Patients With Cutaneous T-Cell Lymphomas: A Single-Center Experience.

Cutaneous T-cell lymphomas (CTCL) represent rare non-Hodgkin lymphomas (NHL) with an incidence less than 1 per 100,000 inhabitants. The most common type of CTCL is mycosis fungoides (MF), which represents approximately 60% of all CTCL, followed by Sézary syndrome (SS), approximately 5%. We retrospectively analyzed the outcome of 118 patients with MF (n=96) and SS (n=22) treated between the years 1998 and 2021 at the Charles University General Hospital in Prague, Czech Republic. The ratio between men and women was 1.2:1 (62 men, and 56 women). The median age at diagnosis was 62 years (23 to 92 years). From the MF cohort 48 patients (50% out of MF cohort) presented with advanced stage disease. Ninety patients (77%) received a systemic treatment at any time from the diagnosis; the median number of therapy lines was two. At the time of database lock, the overall survival (OS) of 96 patients with MF reached 17.7 years with the median follow-up 4.0 years. With the median follow-up 2.6 years, the median OS of 22 patients with SS was 3.5 years. The most common type of systemic therapy for MF included low-dose methotrexate (61%), interferon-alpha (58%), bexarotene (28%), and chlorambucil (25%). The most common type of therapy for SS included bexarotene (64%), extracorporeal photopheresis (50%), and interferon-alpha (45%). Only the minority of patients received innovative targeted agents including brentuximab vedotin, mogamulizumab, or pembrolizumab. Besides the retrospective analysis of the CTCL cohort, current standards and future perspectives of selected innovative agents are summarized and discussed. The analyzed cohort represents the largest cohort of CTCL patients in the Czech Republic. Overall, the survival parameters of our CTCL cohort are comparable to those previously published by other groups. In conclusion, our analysis of 118 real world cohort of consecutive CTCL patients treated at the single center confirmed the efficacy of immune response modifiers and underlines the urgent need for ample implementation of innovative agents and their combinations into earlier lines of therapy.

Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic.

Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant's pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

Targeted Therapies for Melanoma.

The incidence of cutaneous malignant melanoma (CMM) is significantly increasing worldwide.[...].

Cutaneous melanoma dissemination is dependent on the malignant cell properties and factors of intercellular crosstalk in the cancer microenvironment (Review).

The incidence of cutaneous malignant melanoma has been steadily increasing worldwide for several decades. This phenomenon seems to follow the trend observed in many types of malignancies caused by multiple significant factors, including ageing. Despite the progress in cutaneous malignant melanoma therapeutic options, the curability of advanced disease after metastasis represents a serious challenge for further research. In this review, we summarise data on the microenvironment of cutaneous malignant melanoma with emphasis on intercellular signalling during the disease progression. Malignant melanocytes with features of neural crest stem cells interact with non­malignant populations within this microenvironment. We focus on representative bioactive factors regulating this intercellular crosstalk. We describe the possible key factors and signalling cascades responsible for the high complexity of the melanoma microenvironment and its premetastatic niches. Furthermore, we present the concept of melanoma early becoming a systemic disease. This systemic effect is presented as a background for the new horizons in the therapy of cutaneous melanoma.

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes.

Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10-6). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6-413.1; p = 3.2 × 10-7) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4-3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2-6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.

Interleukin-6: a molecule with complex biological impact in cancer.

Interleukin-6 is a multifaceted cytokine, usually reported as a pro-inflammatory molecule. However, certain anti-inflammatory activities were also attributed to IL-6. The levels of IL-6 in serum as well as in other biological fluids are elevated in an age-dependent manner. Notably, it is consistently reported also as a key feature of the senescence-associated secretory phenotype. In the elderly, this cytokine participates in the initiation of catabolism resulting in, e.g. sarcopenia. It can cross the blood-brain barrier, and so it is in causal association with, e.g. depression, bipolar disorder, schizophrenia, and anorexia. In the cancer patient, IL-6 is produced by cancer and stromal cells and actively participates in their crosstalk. IL-6 supports tumour growth and metastasising in terminal patients, and it significantly engages in cancer cachexia (including anorexia) and depression associated with malignancy. The pharmacological treatment impairing IL-6 signalling represents a potential mechanism of anti-tumour therapy targeting cancer growth, metastatic spread, metabolic deterioration and terminal cachexia in patients.

Skin aging: the dermal perspective.

The world population of adults aged 60 years or more is increasing globally, and this development can impact skin disease morbidity and mortality, as well as being reflected in the health care system organization. There is substantial evidence that the burden from a remarkable number of skin nonmalignant and malignant conditions is greater in the elderly. Dermatologic research and clinical education in dermatology should focus on both challenges and opportunities created by aging. Skin aging due to intrinsic and extrinsic factors can alter significantly epidermal and dermal structure and functions. Dermal aging can be linked to a great number of complications in routine dermatologic conditions, with slow healing as an example of a severe complication in the elderly. This may be attributed to aged dermal fibroblasts modifying the tissue microenvironment via a shift in their soluble factors and extracellular matrix repertoire. This senescence-associated secretory phenotype can explain the particular proclivity of aged skin to develop malignancies.