scholarly journals Hyperprogressive Disease: Main Features and Key Controversies

2021 ◽  
Vol 22 (7) ◽  
pp. 3736
Author(s):  
Hugo Arasanz ◽  
Miren Zuazo ◽  
Ana Bocanegra ◽  
Luisa Chocarro ◽  
Ester Blanco ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Associated Factors ◽  
Molecular Mechanisms ◽  
Natural Course ◽  
Preferential Treatment ◽  
Radiological Criteria ◽  
Tumor Histology ◽  
Fast Progression ◽  
Cancer Types ◽  
Hyperprogressive Disease

Along with the positioning of immunotherapy as a preferential treatment for a wide variety of neoplasms, a new pattern of response consisting in a sudden acceleration of tumor growth has been described. This phenomenon has received the name of “hyperprogressive disease”, and several definitions have been proposed for its identification, most of them relying on radiological criteria. However, due to the fact that the cellular and molecular mechanisms have not been elucidated yet, there is still some debate regarding whether this fast progression is induced by immunotherapy or only reflects the natural course of some highly aggressive neoplasms. Moreover, contradictory results of trials including patients with different cancer types suggest that both the incidence, the associated factors and the implications regarding prognosis might differ depending on tumor histology. This article intends to review the main publications regarding this matter and critically approach the most controversial aspects.

scholarly journals Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Virginia Egea ◽  
Kai Kessenbrock ◽  
Devon Lawson ◽  
Alexander Bartelt ◽  
Christian Weber ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Growth ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Human Mesenchymal Stem Cells ◽  
Target Cells ◽  
Autophagic Flux ◽  
Stromal Cell Derived Factor

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

Carboxypeptidase E-ΔN promotes migration, invasiveness, and epithelial–mesenchymal transition of human osteosarcoma cells via the Wnt–β-catenin pathway

2019 ◽  
Vol 97 (4) ◽  
pp. 446-453 ◽  
Author(s):  
Shuli Fan ◽  
Xiang Gao ◽  
Peng Chen ◽  
Xu Li
Keyword(s):  
Cell Migration ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Human Osteosarcoma ◽  
Carboxypeptidase E ◽  
Human Osteosarcoma Cells ◽  
Cancer Types ◽  
Interfering Rna

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents, and metastatic OS is the major cause of OS-related death. Carboxypeptidase E (CPE) is known to be highly expressed in some cancer types, and its N-terminal truncated form, CPE-ΔN, is implicated in tumor metastasis and poor prognosis. In this study, we investigated the effect of CPE-ΔN on cell migration, invasiveness, and the epithelial–mesenchymal transition (EMT) of OS cells, and illustrated the molecular mechanisms. We first constructed CPE-ΔN overexpressing human OS cell lines (143B and U2OS cells), and found that ectopic CPE-ΔN expression in OS cells enhanced cell migration and invasiveness, and promoted the EMT process. Further, overexpression of CPE-ΔN increased the levels of c-myc and nuclear β-catenin in OS cells, which suggested the CPE-ΔN promotes activation of the Wnt–β-catenin pathway in OS cells. Treatment with β-catenin small interfering RNA (siRNA) inhibited the migration and invasiveness of CPE-ΔN-overexpressing cells, and reduced the expression of E-cadherin. Together, these results suggest that CPE-ΔN promotes migration, invasiveness, and the EMT of OS cells via the Wnt–β-catenin signaling pathway.

scholarly journals Integrative analysis of the molecular mechanisms, immunological features and immunotherapy response of ferroptosis regulators across 33 cancer types

2022 ◽  
Vol 18 (1) ◽  
pp. 180-198
Author(s):  
Bufu Tang ◽  
Ruochen Yan ◽  
Jinyu Zhu ◽  
Shimiao Cheng ◽  
Chunli Kong ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Integrative Analysis ◽  
Cancer Types

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

Characterization of hyperprogressive disease in patients with advanced biliary tract cancer treated with anti-PD-1 inhibitor: A multicenter retrospective study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 339-339
Author(s):  
Choong-kun Lee ◽  
Jaekyung Cheon ◽  
Eo Jin Kim ◽  
Chang Gon Kim ◽  
Sunkyu Kim ◽  
...  
Keyword(s):  
Neural Network ◽  
Retrospective Study ◽  
High Risk ◽  
Tumor Growth ◽  
Network Modeling ◽  
Neural Network Modeling ◽  
Clinicopathologic Features ◽  
Tract Cancer ◽  
Hyperprogressive Disease ◽  
Third Line

339 Background: Immunotherapy, including anti-PD-1 inhibitor, represents a promising breakthrough treatment in poor prognostic cancers such as biliary tract cancer (BTC). However, subset of pts suffer from unexpected acceleration of tumor growth following the initiation of immunotherapy, termed hyperprogressive disease (HPD). We assessed HPD in BTC pts treated with anti-PD-1 inhibitor in association with clinicopathologic features. Methods: This retrospective study included pts with BTC who were treated with pembrolizumab 200mg IV as palliative second or third line treatment in 4 tertiary hospitals in South Korea. Previous proposed tumor dynamic parameters including time to treatment failure (TTF), tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated per RECIST v1.1. Neural network modeling technique was adopted to find clinicopathologic features that can predict HPD. Results: Total of 223 pts with BTC were treated with palliative second or third line pembrolizumab between December 2015 to August 2020. ORR was 11.2% (n=1 for CR, n=24 for PR, n=70 for SD, n=118 for PD, and 10 pts not evaluable). Among patients with best response as PD (n=118), 41 patients (18.4% from total pts) met the criteria for HPD definition (>2-fold increase in both TGK and TGR in the experimental period compared to the reference period). HPD pts had worse prognosis compared to non-HPD pts in terms of TTF (median 1.4 vs 2.7 months, P =<0.0001) and OS (median 3.57 vs 5.27 months, P =0.03). Clinicopathologic features including age, ECOG performance status, primary tumor site, pathology, metastatic organ, previous treatment history (surgery or radiotherapy), pretreatment PD-L1 score, tumor markers, and baseline laboratory results (LDH, albumin, or neutrophil-to-lymphocyte ratio) did not predict HPD (compared to non-HPD pts or PD without HPD pts). By neural network modeling and plotting with hidden vectors, we could define HPD-high-risk cluster (n=37) and HPD-lower-risk cluster (n=80). Higher CA 19-9-to-lymphocyte ratio ( P =0.0004) or higher platelet-to-PD-L1 CPS (combined positivity score) ratio ( P =0.002) predicted HPD-high-risk-cluster. HPD pts (n=41) tend to have progression due to liver (73.2% vs 45.6%, P =0.0026) or peritoneum (53.7% vs 21.4%, P=<0.0001) metastases, compared to non-HPD pts (n=182). Conclusions: This study for the first time describe the clinicopathologic features of HPD among pembrolizumab treated BTC pts. Baseline pathology and laboratory tests may help optimal patient selection for immunotherapy to avoid HPD in BTC pts. Further validation of BTC-specific HPD predictive features and definition (TGK or TGR ratio cut-off) will be presented after comparison with clinicopathologic features among second line 5FU-based chemotherapy treated BTC pts.

scholarly journals ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3415
Author(s):  
Ge Dong ◽  
Gui Ma ◽  
Rui Wu ◽  
Jinming Liu ◽  
Mingcheng Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Mammary Epithelial Cells ◽  
Progesterone Receptors ◽  
Mammary Epithelial ◽  
Luciferase Reporter ◽  
Mammosphere Formation

Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice; and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells’ proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.

scholarly journals Molecular Mechanisms of Heat Shock Factors in Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1202
Author(s):  
Mikael Christer Puustinen ◽  
Lea Sistonen
Keyword(s):  
Heat Shock ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Heat Shock Factors ◽  
Therapeutic Approaches ◽  
The Past ◽  
Cancer Types ◽  
Cellular Pathways ◽  
As Stress ◽  
Regulatory Functions

Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

Comparison of Fast-Progression, Hyperprogressive Disease, and Early Deaths in Advanced Non–Small-Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or Chemotherapy

2020 ◽  
pp. 829-840 ◽  
Author(s):  
Roberto Ferrara ◽  
Laura Mezquita ◽  
Matthieu Texier ◽  
Jihene Lahmar ◽  
Clarisse Audigier-Valette ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Ct Scan ◽  
Cell Lung Cancer ◽  
Group Performance ◽  
Single Agent ◽  
Small Cell ◽  
Small Cell Lung ◽  
Fast Progression ◽  
Hyperprogressive Disease

PURPOSE Hyperprogressive disease (HPD), fast progression (FP), and early death (ED) have been described in 13.8%, 4.7%, and 5.6% and in 5.1%, 2.8%, and 6.8%, respectively, of patients with non–small-cell lung cancer (NSCLC) treated with single-agent programmed cell death ligand 1 inhibitors (ICI) or chemotherapy, respectively. Whether FP/ED and HPD represent overlapping patterns is unknown. PATIENTS AND METHODS FP, ED, and HPD were retrospectively assessed in patients with NSCLC treated with single-agent ICI or chemotherapy. Eligibility required 2 computed tomography (CT) scans before and 1 CT scan during treatment. (1) HPD, (2) FP, (3) ED were defined as (1) RECIST version 1.1 progression at first CT scan and tumor growth rate variation per month > 50%, (2) ≥ 50% increase in the sum of the longest diameters of target lesions within 6 weeks from baseline, and (3) death as a result of radiologic progression within 12 weeks from baseline CT scan, respectively. RESULTS Of 406 ICI-treated NSCLC, 56 patients (13.8%), 9 patients (2.2%), and 36 patients (8.8%) were HPD, FP, and ED, respectively. Eight (14.2%) and 20 (35.7%) of 56 patients with HPD were also FP and ED. ED significantly correlated with baseline Eastern Cooperative Oncology Group performance status ≥ 2 compared with HPD (33% v 13%, P = .02). Overall survival was significantly longer for HPD (3.4 months [95% CI, 2.7 to 4.0 months]) compared with FP (0.7 months [95% CI, 0.6 to 0.8 months]); HR, 0.18 [95% CI, 0.08 to 0.42]; P < .0001) and ED (1.4 months [95% CI, 1.3 to 1.6 months]); HR, 0.19 [95% CI, 0.11 to 0.34]); P < .0001), whereas it did not differ between FP and ED (HR, 1.3 [95% CI, 0.56 to 3.0]; P = .55). Of 59 patients with NSCLC treated with single-agent chemotherapy, the HPD, FP, and ED rates were 5.1%, 1.7%, and 6.7%, respectively. CONCLUSION FP, ED, and HPD represent distinct progression patterns with limited overlap and different survival outcomes.

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