Cancers

Harris, Ashlee;Andl, Thomas

doi: 10.3390/cancers15082192pmid: 37190121

Head and neck squamous cell carcinomas (HNSCCs) develop through a series of precancerous stages from a pool of potentially malignant disorders (PMDs). Although we understand the genetic changes that lead to HNSCC, our understanding of the role of the stroma in the progression from precancer to cancer is limited. The stroma is the primary battleground between the forces that prevent and promote cancer growth. Targeting the stroma has yielded promising cancer therapies. However, the stroma at the precancerous stage of HNSCCs is poorly defined, and we may miss opportunities for chemopreventive interventions. PMDs already exhibit many features of the HNSCC stroma, such as inflammation, neovascularization, and immune suppression. Still, they do not induce cancer-associated fibroblasts or destroy the basal lamina, the stroma’s initial structure. Our review aims to summarize the current understanding of the transition from precancer to cancer stroma and how this knowledge can reveal opportunities and limitations for diagnostic, prognostic, and therapeutic decisions to benefit patients. We will discuss what may be needed to fulfill the promise of the precancerous stroma as a target to prevent progression to cancer.

Gimeno-García, Antonio Z.;Hernández-Pérez, Anjara;Nicolás-Pérez, David;Hernández-Guerra, Manuel

doi: 10.3390/cancers15082193pmid: 37190122

Growing evidence indicates that artificial intelligence (AI) applied to medicine is here to stay. In gastroenterology, AI computer vision applications have been stated as a research priority. The two main AI system categories are computer-aided polyp detection (CADe) and computer-assisted diagnosis (CADx). However, other fields of expansion are those related to colonoscopy quality, such as methods to objectively assess colon cleansing during the colonoscopy, as well as devices to automatically predict and improve bowel cleansing before the examination, predict deep submucosal invasion, obtain a reliable measurement of colorectal polyps and accurately locate colorectal lesions in the colon. Although growing evidence indicates that AI systems could improve some of these quality metrics, there are concerns regarding cost-effectiveness, and large and multicentric randomized studies with strong outcomes, such as post-colonoscopy colorectal cancer incidence and mortality, are lacking. The integration of all these tasks into one quality-improvement device could facilitate the incorporation of AI systems in clinical practice. In this manuscript, the current status of the role of AI in colonoscopy is reviewed, as well as its current applications, drawbacks and areas for improvement.

Zhang, Wei;Li, Emma;Wang, Lily;Lehmann, Brian D.;Chen, X. Steven

doi: 10.3390/cancers15082194pmid: 37190123

Triple-negative breast cancer (TNBC) is a heterogeneous disease with varying responses to neoadjuvant chemotherapy (NAC). The identification of biomarkers to predict NAC response and inform personalized treatment strategies is essential. In this study, we conducted large-scale gene expression meta-analyses to identify genes associated with NAC response and survival outcomes. The results showed that immune, cell cycle/mitotic, and RNA splicing-related pathways were significantly associated with favorable clinical outcomes. Furthermore, we integrated and divided the gene association results from NAC response and survival outcomes into four quadrants, which provided more insights into potential NAC response mechanisms and biomarker discovery.

Alizadeh, Javad;Kavoosi, Mahboubeh;Singh, Navjit;Lorzadeh, Shahrokh;Ravandi, Amir;Kidane, Biniam;Ahmed, Naseer;Mraiche, Fatima;Mowat, Michael R.;Ghavami, Saeid

doi: 10.3390/cancers15082195pmid: 37190124

Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.

Alves, Bárbara;Peixoto, Joana;Macedo, Sofia;Pinheiro, Jorge;Carvalho, Bruno;Soares, Paula;Lima, Jorge;Lima, Raquel T.

doi: 10.3390/cancers15082196pmid: 37190125

Glioblastoma (GB) is one of the deadliest human cancers. Many GB patients do not respond to treatment, and inevitably die within a median of 15–18 months post-diagnosis, highlighting the need for reliable biomarkers to aid clinical management and treatment evaluation. The GB microenvironment holds tremendous potential as a source of biomarkers; several proteins such as MMP-2, MMP-9, YKL40, and VEGFA have been identified as being differentially expressed in GB patient samples. Still to date, none of these proteins have been translated into relevant clinical biomarkers. This study evaluated the expression of MMP-2, MMP-9, YKL40, and VEGFA in a series of GBs and their impact on patient outcome. High levels of VEGFA expression were significantly associated with improved progression-free survival after bevacizumab treatment, thus having potential as a tissue biomarker for predicting patients’ response to bevacizumab. Noteworthily, VEGFA expression was not associated with patient outcome after temozolomide treatment. To a lesser extent, YKL40 also provided significant information regarding the extent of bevacizumab treatment. This study highlights the importance of studying secretome-associated proteins as GB biomarkers and identifies VEGFA as a promising marker for predicting response to bevacizumab.

Bezzio, Cristina;Vernero, Marta;Ribaldone, Davide Giuseppe;Alimenti, Eleonora;Manes, Gianpiero;Saibeni, Simone

doi: 10.3390/cancers15082197pmid: 37190126

Tofacitinib is approved for several immune-mediated inflammatory diseases, but safety concerns have recently been raised. We searched PubMed (accessed on 27 February 2023) for original articles regarding tofacitinib’s cancer risk when used for rheumatoid arthritis, ulcerative colitis, Crohn’s disease, psoriatic arthritis, and ankylosing spondylitis. Of the 2047 initial records, 22 articles describing 26 controlled studies (including 22 randomized controlled trials) were selected. In the comparison between tofacitinib and any control treatment, the relative risk (RR) for any cancer was 1.06 (95% CI, 0.86–1.31; p = 0.95). In separate comparisons between tofacitinib and either a placebo or biological therapy, no difference was found in the overall cancer risk (vs. placebo, RR = 1.04; 95% CI, 0.44–2.48; p = 0.95; vs. biological drugs, RR = 1.06; 95% CI, 0.86–1.31; p = 0.58). When tofacitinib was compared to tumor necrosis factor (TNF) inhibitors, the overall cancer RR was 1.40 (95% CI, 1.06–2.08; p = 0.02). Similarly, significant results were obtained for all cancers, except for non-melanoma skin cancer (RR = 1.47; 95% CI, 1.05–2.06; p = 0.03), and for this skin cancer alone (RR = 1.30; 95% CI, 0.22–5.83; p = 0.88). In conclusion, no difference in the overall cancer risk was found between tofacitinib and either a placebo or biological drugs, while a slightly higher risk was found in patients treated with tofacitinib than anti-TNF agents. Further studies are needed to better define the cancer risk of tofacitinib therapy.

Gupta, Anvita;Carnazza, Michelle;Jones, Melanie;Darzynkiewicz, Zbigniew;Halicka, Dorota;O’Connell, Timmy;Zhao, Hong;Dadafarin, Sina;Shin, Edward;Schwarcz, Monica D.;Moscatello, Augustine;Tiwari, Raj K.;Geliebter, Jan

doi: 10.3390/cancers15082198pmid: 37190127

Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

Mereu, Elisabetta;Abbo, Damiano;Paradzik, Tina;Cumerlato, Michela;Bandini, Cecilia;Labrador, Maria;Maccagno, Monica;Ronchetti, Domenica;Manicardi, Veronica;Neri, Antonino;Piva, Roberto

doi: 10.3390/cancers15082199pmid: 37190128

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients.

Boraschi, Piero;Moretto, Roberto;Donati, Francescamaria;Borelli, Beatrice;Mercogliano, Giuseppe;Giugliano, Luigi;Boccaccino, Alessandra;Della Pina, Maria Clotilde;Colombatto, Piero;Signori, Stefano;Masi, Gianluca;Cremolini, Chiara;Urbani, Lucio

doi: 10.3390/cancers15082200pmid: 37190129

Heung, Yvonne;Zhukovsky, Donna;Hui, David;Lu, Zhanni;Andersen, Clark;Bruera, Eduardo

doi: 10.3390/cancers15082201pmid: 37190130

To evaluate how the COVID-19 pandemic impacted the quality of end-of-life care for patients with advanced cancer, we compared a random sample of 250 inpatient deaths from 1 April 2019, to 31 July 2019, with 250 consecutive inpatient deaths from 1 April 2020, to 31 July 2020, at a comprehensive cancer center. Sociodemographic and clinical characteristics, the timing of palliative care referral, timing of do-not-resuscitate (DNR) orders, location of death, and pre-admission out-of-hospital DNR documentation were included. During the COVID-19 pandemic, DNR orders occurred earlier (2.9 vs. 1.7 days before death, p = 0.028), and palliative care referrals also occurred earlier (3.5 vs. 2.5 days before death, p = 0.041). During the pandemic, 36% of inpatient deaths occurred in the Intensive Care Unit (ICU) and 36% in the Palliative Care Unit, compared to 48 and 29%, respectively, before the pandemic (p = 0.001). Earlier DNR orders, earlier palliative care referrals, and fewer ICU deaths suggest an improvement in the quality of end-of-life care in response to the COVID-19 pandemic. These encouraging findings may have future implications for maintaining quality end-of-life care post-pandemic.