Browsing by Author "Henriques, Vanessa"

Now showing 1 - 4 of 4
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    Cell competition and tumor heterogeneity
    (Elsevier, 2019) Parker, Taylor M.; Henriques, Vanessa; Beltran, Antonio; Nakshatri, Harikrishna; Gogna, Rajan; Surgery, School of Medicine
    Cancers exhibit a remarkable degree of intratumoral heterogeneity (ITH), which results from complex cellular interactions amongst various cell types. This phenomenon provides an opportunity for clonal selection and growth advantages to aggressive cancer cell types, resulting in worse prognosis and challenges to anti-cancer therapy. Cell competition is a conserved mechanism operational in cellular and organ systems, which allows neighboring cells to compare their relative fitness levels and results in the elimination of viable but suboptimal cells. By abuse of this conserved homeostasis mechanism, aggressive cancer cell types gain an advantage over normal cell types by achieving traits like increased proliferation, de-differentiation, and stemness. This review presents recent evidence that cell competition mechanisms actively participate in the regulation of intratumoral cell-cell interactions and thus contribute to ITH, and this process is essential for cancer development and progression.
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    HIF-transcribed p53 chaperones HIF-1α
    (Oxford University Press, 2019-11-04) Madan, Esha; Parker, Taylor M.; Pelham, Christopher J.; Palma, Antonio M.; Peixoto, Maria L.; Nagane, Masaki; Chandaria, Aliya; Tomás, Ana R.; Canas-Marques, Rita; Henriques, Vanessa; Galzerano, Antonio; Cabral-Teixeira, Joaquim; Selvendiran, Karuppaiyah; Kuppusamy, Periannan; Carvalho, Carlos; Beltran, Antonio; Moreno, Eduardo; Pati, Uttam K.; Gogna, Rajan; Surgery, School of Medicine
    Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.
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    The Identification of Immunological Biomarkers in Kidney Cancers
    (Frontiers Media, 2018-11-02) Lopez-Beltran, Antonio; Henriques, Vanessa; Cimadamore, Alessia; Santoni, Matteo; Cheng, Liang; Gevaert, Thomas; Blanca, Ana; Massari, Francesco; Scarpelli, Marina; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice.
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    Predicting biochemical recurrence after radical prostatectomy: the role of prognostic grade group and index tumor nodule
    (Elsevier, 2019-11) Vau, Nuno; Henriques, Vanessa; Cheng, Liang; Blanca, Ana; Fonseca, Jorge; Montironi, Rodolfo; Cimadamore, Alessia; Lopez-Beltran, Antonio; Pathology and Laboratory Medicine, School of Medicine
    The aim of the current study was to test whether the grade group assessed in the index tumor nodule predicts biochemical recurrence after surgery. The study cohort series included 144 consecutive patients treated by laparoscopic radical prostatectomy. The following parameters were evaluated in each case: type of radical prostatectomy (with/without lymphadenectomy), pT and pN status, histologic type of prostate carcinoma (acinar versus mixed histology), surgical margin resection status, perineural invasion, lymphovascular invasion, biochemical recurrence status, presence of tertiary Gleason 5 pattern, and grade group that was assessed both in overall prostate cancer and in index (dominant) tumor nodule. Twenty patients (13.9%) experienced postoperative biochemical recurrence at a mean follow-up time of 12.2 months. The univariate survival analysis selected type of radical prostatectomy, histological subtype, lymphovascular invasion, American Joint Committee on Cancer pT and pN classification, tertiary Gleason 5 pattern, preoperative serum prostate specific antigen level, and the grade group assessed in both the overall prostate and index tumor nodule as significant for biochemical recurrence-free survival. Type of radical prostatectomy (P = .020), histological subtype (P = .002), lymphovascular invasion (P = .023), tertiary Gleason pattern 5 (P = .016), and grade group classification in index tumor nodule (P ≤ .0001) were selected as independent predictors of biochemical recurrence-free survival. In conclusion, our results validate grade group in the index tumor nodule as an independent predictor of biochemical recurrence-free survival, thus emphasizing the value of reporting grade group in index tumor nodule. The main limitation of our study is the relatively low number of cases in the current series, suggesting the need of large confirmatory studies.