Evolutionary origins of metabolic reprogramming in cancer

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These molecular mechanisms have been acquired during metazoan evolution, first to eliminate the infection of the tissue injury, then to enter an effective regenerative phase. Cancer itself could be considered a phenomenon of antagonistic pleiotropy of the genes involved in effective tissue repair. Cancer and tissue repair are complex traits that share many intermediate phenotypes at the molecular, cellular, and tissue levels, and all of these are integrated within a Systems Biology structure. Complex traits are influenced by a multitude of common genes, each with a weak effect. This polygenic component of complex traits is mainly unknown and so makes up part of the missing heritability. Here, we try to integrate these different perspectives from the point of view of the metabolic changes observed in cancer.This work was supported in JPL’s lab by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR.”, the Regional Government of Castile and León (CSI234P18 and CSI144P20). SCLl was the recipient of a Ramón y Cajal research contract from the Spanish Ministry of Economy and Competitiveness and was supported by grant RTI2018-094130-B-100 funded by MCIN/AEI/10.13039/501100011039 and by “ERDF A way of making Europe.” RCC and AJN are funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). MJPB is funded by grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/501100011039. J.C. is partially supported by grant GRS2139/A/20 (Gerencia Regional de Salud de Castilla y León) and by the Instituto de Salud Carlos III (PI18/00587 and PI21/01207), co-financed by FEDER funds, and by the “Programa de Intensificación” of the ISCIII, grant number INT20/00074. We thank Phil Mason for English language support

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study

Background: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. Aim: To assess the daily clinical practice approach to LyP and the response to first-line treatments. Methods: This was a retrospective study enrolling 252 patients with LyP. Results: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. Conclusions: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse

Brentuximab vedotin in the treatment of cutaneous T-cell lymphomas: Data from the Spanish Primary Cutaneous Lymphoma Registry

[Background] Brentuximab vedotin (BV) has been approved for CD30-expressing cutaneous T-cell lymphoma (CTCL) after at least one previous systemic treatment. However, real clinical practice is still limited.[Objectives] To evaluate the response and tolerance of BV in a cohort of patients with CTCL.[Methods] We analysed CTCL patients treated with BV from the Spanish Primary Cutaneous Lymphoma Registry (RELCP).[Results] Sixty-seven patients were included. There were 26 females and the mean age at diagnosis was 59 years. Forty-eight were mycosis fungoides (MF), 7 Sézary syndrome (SS) and 12 CD30+ lymphoproliferative disorders (CD30 LPD). Mean follow-up was 18 months. Thirty patients (45%) showed at least 10% of CD30+ cells among the total lymphocytic infiltrate. The median number of BV infusions received was 7. The overall response rate (ORR) was 67% (63% in MF, 71% in SS and 84% in CD30 LPD). Ten of 14 patients with folliculotropic MF (FMF) achieved complete or partial response (ORR 71%). The median time to response was 2.8 months. During follow-up, 36 cases (54%) experienced cutaneous relapse or progression. The median progression free survival (PFS) was 10.3 months. The most frequent adverse event was peripheral neuropathy (PN) (57%), in most patients (85%), grades 1 or 2.[Conclusions] These results confirm the efficacy and safety of BV in patients with advanced-stage MF, and CD30 LPD. In addition, patients with FMF and SS also showed a favourable response. Our data suggest that BV retreatment is effective in a proportion of cases.The Spanish Primary Cutaneous Lymphoma Registry (RELCP) is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which received an unrestricted grant support from Kyowa Kirin.Peer reviewe

PATTERNS OF INCIDENTAL PERINEURAL INVASION AND PROGNOSIS IN CUTANEOUS SQUAMOUS CELL CARCINOMA: A MULTICENTER, RETROSPECTIVE COHORT STUDY

Supplementary material. A. Conde-Ferreirós(*), L.A. Corchete (*), A. Jaka , Á. Santos-Briz,, MªJosé Fuente, R. Posada, Laura Pons, S. Podlipnik, R. M. Pujol, C. Román-Curto, A. Toll, J. Cañueto. PATTERNS OF INCIDENTAL PERINEURAL INVASION AND PROGNOSIS IN CUTANEOUS SQUAMOUS CELL CARCINOMA: A MULTICENTER, RETROSPECTIVE COHORT STUDY

DEFINITION OF PROGNOSTIC SUBGROUPS IN THE T3-AJCC8 STAGE FOR CUTANEOUS SQUAMOUS CELL CARCINOMA: TENTATIVE T3 STAGE SUBCLASSIFICATION

Supplementary material: DEFINITION OF PROGNOSTIC SUBGROUPS IN THE T3-AJCC8 STAGE FOR CUTANEOUS SQUAMOUS CELL CARCINOMA: TENTATIVE T3 STAGE SUBCLASSIFICATIONTHIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

MicroRNA dysregulation in cutaneous squamous cell carcinoma

© 2019 by the authors.Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.Javier Cañueto is partially supported by the grants PI18/000587 (Instituto de Salud Carlos III cofinanciado con fondos FEDER) and GRS 1835/A/18 (Gerencia Regional de Salud de Castilla y León), and by the Programa de Intensificación de la Actividad Investigadora de la Gerencia Regional de Salud de Castilla y León (INT/M/10/19), Spai

Cutaneous squamous cell carcinoma: From biology to therapy

This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches.Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors. Another purpose of this review is to explore the landscape of drugs that may induce or contribute to the development of CSCC. Beginning with the pathogenetic basis of these drug-induced CSCCs, we move on to consider potential therapeutic opportunities for overcoming this adverse effect.Javier Cañueto is partially supported by the grants PI18/000587 (Instituto de Salud Carlos III cofinanciado con fondos FEDER) and GRS 1835/A/18 (Gerencia Regional de Salud de Castilla y León).Peer reviewe

Rapid growth rate is associated with poor prognosis in cutaneous squamous cell carcinoma

[Background]: Cutaneous squamous cell carcinoma (cSCC) represents the most common form of skin cancer after basal cell carcinoma, and can be both locally invasive and metastatic to distant sites. Growth rate (GR) has been poorly evaluated in cSCC, despite clinical evidence suggesting that GR is an important risk factor in cSCC.[Aim]: To analyse the influence of GR in cSCC prognosis.[Methods]: We retrospectively evaluated GR in a series of 90 cSCCs and tried to correlate GR with prognosis in cSCC.[Results]: We demonstrated that tumours with a GR of > 4 mm/month exhibit a higher risk of nodal progression and a shorter progression time to lymph node metastasis in cSCC than those with GR of < 4 mm/month. As expected, GR correlated with tumour proliferation, as determined by Ki-67 expression.[Conclusions]: We consider a GR of 4 mm/month as the cutoff point that distinguishes between rapid- and slow-progressing tumours and, more importantly, to identify a subset of high-risk cSCCs.JC was partially supported by Gerencia Regional de Salud, Junta de Castilla y León (GRS 1342/A/16) and by the programme INT/M/16/17. JPL was partially supported by FEDER and MICINN (SAF2014–56989-R), Instituto de Salud Carlos III (PIE14/00066), Junta de Castilla y León (BIO/SA31/15, CSI001416), IBSAL (IBY15/00003), the Eugenio Rodríguez Pascual, the Fundación Sandra Ibarra de Solidaridad frente al Cáncer and We can be Heroes Foundation. CR-C is funded by Q3718001E (2009–2010) and GRS 612/A/11 (2011–2012) and the Fundación Eugenio Rodríguez Pascual

CD133+ cell content correlates with tumour growth in melanomas from skin with chronic sun-induced damage

[Background]: Melanoma is responsible for almost 80% of the deaths attributed to skin cancer. Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. [Objectives]: We hypothesized that the phenotypic heterogeneity of human cutaneous melanomas is related to their content of CD133+ cells. [Methods]: We compared the percentages of CD133+ cells in 29 tumours from four classic types of melanoma: lentigo maligna melanoma (LMM), superficial spreading melanoma, nodular melanoma and acral lentiginous melanoma (ALM). Also, we compared the percentages of CD133+ cells in melanomas with different degrees of exposure to ultraviolet radiation: 16 melanomas from skin with chronic sun-induced damage and 13 melanomas from skin without such damage. [Results]: We found a statistically significant increase of CD133+ cells in three different contexts: in melanomas arising on skin with signs of chronic sun-induced damage vs. nonexposed skin, in melanomas in situ vs. invasive melanomas, and in LMM vs. ALM. The proportions of CD133+ cells did not differ among samples of normal skin with different degrees of sun exposure. A distinct subpopulation of CD133+CXCR4+ cancer stem cells (CSCs) was identified and shown to be related to the invasive phenotype of the tumours. [Conclusions]: Here, we provide evidence showing, for the first time, that an increase in the CD133+ cell content is associated both with melanomas arising on skin with signs of chronic sun-induced damage and in melanomas in situ with better prognosis. Moreover, our study further confirms the existence of a subpopulation of CD133+CXCR4+ CSCs in cutaneous melanomas with invasive phenotype and poor prognosis. What's already known about this topic? Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. What does this study add? In the present study, we provide evidence showing, for the first time, that an increase in the content of CD133+ cells is associated with melanomas arising on skin with signs of chronic sun-induced damage and in melanomas in situ with better prognosis. This study also confirms the existence of a subpopulation of CD133+CXCR4+ cancer stem cells in melanomas with invasive phenotype and poor prognosis.Research in the ISG group is partially supported by FEDER and by MICINN SAF2012-32810, by MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), by an NIH grant (R01 CA109335-04A1), the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Programme) and by proyecto en red de investigación en celulas madre tumorales supported by Obra Social Kutxa y Conserjería de Sanidad de la Junta de Castilla y Leon. All Spanish funding is cosponsored by the European Union FEDER programme. ISG is an API lab of the EuroSyStem project.Peer Reviewe