Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

Download Full-text

The Role of Metabolic Factors in Renal Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms21197246 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7246

Author(s):

Jacek Rysz ◽

Beata Franczyk ◽

Janusz Ławiński ◽

Robert Olszewski ◽

Anna Gluba-Brzózka

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Malignant Tumours ◽

Metabolic Factors ◽

Lipid Disorders ◽

Igf System ◽

Low Body Mass Index ◽

The Impact

An increasing number of evidence indicates that metabolic factors may play an important role in the development and progression of certain types of cancers, including renal cell carcinoma (RCC). This tumour is the most common kidney cancer which accounts for approximately 3–5% of malignant tumours in adults. Numerous studies indicated that concomitant diseases, including diabetes mellitus (DM) and hypertension, as well as obesity, insulin resistance, and lipid disorders, may also influence the prognosis and cancer-specific overall survival. However, the results of studies concerning the impact of metabolic factors on RCC are controversial. It appears that obesity increases the risk of RCC development; however, it may be a favourable factor in terms of prognosis. Obesity is closely related to insulin resistance and the development of diabetes mellitus type 2 (DM2T) since the adipocytes in visceral tissue secrete substances responsible for insulin resistance, e.g., free fatty acids. Interactions between insulin and insulin-like growth factor (IGF) system appear to be of key importance in the development and progression of RCC; however, the exact role of insulin and IGFs in RCC pathophysiology remains elusive. Studies indicated that diabetes increased the risk of RCC, but it might not alter cancer-related survival. The risk associated with a lipid profile is most mysterious, as numerous studies provided conflicting results. Even though large studies unravelling pathomechanisms involved in cancer growth are required to finally establish the impact of metabolic factors on the development, progression, and prognosis of renal cancers, it seems that the monitoring of health conditions, such as diabetes, low body mass index (BMI), and lipid disorders is of high importance in clear-cell RCC.

Download Full-text

Pathophysiology of β2-glycoprotein I in antiphospholipid syndrome

Lupus ◽

10.1177/0961203310361352 ◽

2010 ◽

Vol 19 (4) ◽

pp. 379-384 ◽

Cited By ~ 17

Author(s):

E. Matsuura ◽

L. Shen ◽

Y. Matsunami ◽

N. Quan ◽

M. Makarova ◽

...

Keyword(s):

Vascular Disease ◽

Antiphospholipid Syndrome ◽

Mechanism Of Action ◽

Antiphospholipid Antibodies ◽

Physiological Role ◽

Therapeutic Strategies ◽

Physiological Functions ◽

Glycoprotein I ◽

The Impact

Since β2-glycoprotein I (β2GPI) was described as the major antigenic target for antiphospholipid antibodies, many studies have focused their attention to the physiological role of β2GPI and anti-β2GPI antibodies on autoimmune-mediated thrombosis. Studies reporting the physiological role of β2GPI have been numerous, but the exact mechanism of action(s) has yet to be completely determined. β2GPI’s epitopes for anti-β2GPI autoantibodies have been characterized, however, not all of the heterogeneous anti-β2GPI antibodies are pathogenic. The pathophysiologic role of β2GPI has been reported in the fields of coagulation, fibrinolysis, angiogenesis, and atherosclerosis. Our understanding of the impact of β2GPI, its metabolites and autoantibodies to β2GPI on these physiological functions may contribute to the development of better therapeutic strategies to treat and prevent autoimmune-mediated atherothrombotic vascular disease. Lupus (2010) 19, 379—384.

Download Full-text

Advances and challenges in cancer treatment and nutraceutical prevention: the possible role of dietary phenols in BRCA regulation

Phytochemistry Reviews ◽

10.1007/s11101-021-09771-3 ◽

2021 ◽

Author(s):

Haroon Khan ◽

Fabiana Labanca ◽

Hammad Ullah ◽

Yaseen Hussain ◽

Nikolay T. Tzvetkov ◽

...

Keyword(s):

Cell Cycle ◽

Natural Products ◽

Cancer Treatment ◽

Clinical Aspects ◽

Anti Cancer ◽

Brca 1 ◽

Brca 2 ◽

The Impact ◽

Cancer Activity

AbstractOver the years, the attention towards the role of phytochemicals in dietary natural products in reducing the risk of developing cancer is rising. Cancer is the second primary cause of mortality worldwide. The current therapeutic options for cancer treatment are surgical excision, immunotherapy, chemotherapy, and radiotherapy. Unfortunately, in case of metastases or chemoresistance, the treatment options become very limited. Despite the advances in medical and pharmaceutical sciences, the impact of available treatments on survival is not satisfactory. Recently, natural products are a great deal of interest as potential anti-cancer agents. Among them, phenolic compounds have gained a great deal of interest, thanks to their anti-cancer activity. The present review focuses on the suppression of cancer by targeting BRCA gene expression using dietary polyphenols, as well as the clinical aspects of polyphenolic agents in cancer therapy. They regulate specific key processes involved in cancer progression and modulate the expression of oncogenic proteins, like p27, p21, and p53, which may lead to apoptosis, cell cycle arrest, inhibition of cell proliferation, and, consequently, cancer suppression. Thus, one of the mechanisms underlying the anti-cancer activity of phenolics involves the regulation of tumor suppressor genes. Among them, the BRCA genes, with the two forms (BRCA-1 and BRCA-2), play a pivotal role in cancer protection and prevention. BRCA germline mutations are associated with an increased risk of developing several types of cancers, including ovarian, breast, and prostate cancers. BRCA genes also play a key role in the sensitivity and response of cancer cells to specific pharmacological treatments. As the importance of BRCA-1 and BRCA-2 in reducing cancer invasiveness, repairing DNA damages, oncosoppression, and cell cycle checkpoint, their regulation by natural molecules has been examined.

Download Full-text

The Therapeutic Impact of New Migraine Discoveries

Current Medicinal Chemistry ◽

10.2174/0929867325666180530114534 ◽

2019 ◽

Vol 26 (34) ◽

pp. 6261-6281 ◽

Cited By ~ 4

Author(s):

László Vécsei ◽

Melinda Lukács ◽

János Tajti ◽

Ferenc Fülöp ◽

József Toldi ◽

...

Keyword(s):

Clinical Trials ◽

Preventive Treatment ◽

Therapeutic Strategies ◽

Migraine Treatment ◽

Preclinical Studies ◽

Therapeutic Approaches ◽

Trigeminovascular System ◽

Glutamate Receptor Antagonists

Background: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. Objective: The present study is a review of the current literature regarding new therapeutic lines in migraine research. Methods: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. Results: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Conclusion: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.

Download Full-text

The role of epithelial–mesenchymal transition-regulating transcription factors in anti-cancer drug resistance

Archives of Pharmacal Research ◽

10.1007/s12272-021-01321-x ◽

2021 ◽

Author(s):

Jihye Seo ◽

Jain Ha ◽

Eunjeong Kang ◽

Sayeon Cho

Keyword(s):

Drug Resistance ◽

Transcription Factors ◽

Epithelial Mesenchymal Transition ◽

Cancer Drug ◽

Preclinical Studies ◽

Mesenchymal Transition ◽

Cancer Drug Resistance ◽

Anti Cancer ◽

Future Challenges

AbstractThe complex orchestration of gene expression that mediates the transition of epithelial cells into mesenchymal cells is implicated in cancer development and metastasis. As the primary regulator of the process, epithelial-mesenchymal transition-regulating transcription factors (EMT-TFs) play key roles in metastasis. They are also highlighted in recent preclinical studies on resistance to cancer therapy. This review describes the role of three main EMT-TFs, including Snail, Twist1, and zinc-finger E homeobox-binding 1 (ZEB1), relating to drug resistance and current possible approaches for future challenges targeting EMT-TFs.

Download Full-text

The Challenging Riddle about the Janus-Type Role of Hsp60 and Related Extracellular Vesicles and miRNAs in Carcinogenesis and the Promises of Its Solution

Applied Sciences ◽

10.3390/app11031175 ◽

2021 ◽

Vol 11 (3) ◽

pp. 1175

Author(s):

Sabrina David ◽

Alessandra Maria Vitale ◽

Alberto Fucarino ◽

Federica Scalia ◽

Giuseppe Vergilio ◽

...

Keyword(s):

Cell Membrane ◽

Extracellular Vesicles ◽

Cancer Development ◽

Cancer Therapies ◽

Ongoing Research ◽

Pathological Conditions ◽

Anti Cancer ◽

Evolutionarily Conserved ◽

The Impact

Hsp60 is one of the most ancient and evolutionarily conserved members of the chaperoning system. It typically resides within mitochondria, in which it contributes to maintaining the organelle’s proteome integrity and homeostasis. In the last few years, it has been shown that Hsp60 also occurs in other locations, intracellularly and extracellularly, including cytosol, plasma-cell membrane, and extracellular vesicles (EVs). Consequently, non-canonical functions and interacting partners of Hsp60 have been identified and it has been realized that it is a hub molecule in diverse networks and pathways and that it is implicated, directly or indirectly, in the development of various pathological conditions, the Hsp60 chaperonopathies. In this review, we will focus on the multi-faceted role of this chaperonin in human cancers, showing the contribution of intra- and extracellular Hsp60 in cancer development and progression, as well as the impact of miRNA-mediated regulation of Hsp60 in carcinogenesis. There are still various aspects of this intricate biological scenario that are poorly understood but ongoing research is steadily providing new insights and we will direct attention to them. For instance, we will highlight the possible applications of the Hsp60 involvement in carcinogenesis not only in diagnosis, but also in the development of specific anti-cancer therapies centered on the use of the chaperonin as therapeutic target or agent and depending on its role, pro- or anti-tumor.

Download Full-text

The Green Anti-Cancer Weapon. The Role of Natural Compounds in Bladder Cancer Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22157787 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7787

Author(s):

Paulina Wigner ◽

Michal Bijak ◽

Joanna Saluk-Bijak

Keyword(s):

Bladder Cancer ◽

Treatment Success ◽

Recurrence Risk ◽

Preclinical Studies ◽

Natural Origin ◽

Genitourinary Cancer ◽

Natural Substances ◽

Anti Cancer ◽

The World

Bladder cancer (BC) is the second most common genitourinary cancer. In 2018, 550,000 people in the world were diagnosed with BC, and the number of new cases continues to rise. BC is also characterized by high recurrence risk, despite therapies. Although in the last few years, the range of BC therapy has considerably widened, it is associated with severe side effects and the development of drug resistance, which is hampering treatment success. Thus, patients are increasingly choosing products of natural origin as an alternative or complementary therapeutic options. Therefore, in this article, we aim to elucidate, using the available literature, the role of natural substances such as curcumin, sulforaphane, resveratrol, quercetin, 6-gingerol, delphinidin, epigallocatechin-3-gallate and gossypol in the BC treatment. Numerous clinical and preclinical studies point to their role in the modulation of the signaling pathways, such as cell proliferation, cell survival, apoptosis and cell death.

Download Full-text

High Nuclear Expression of Yes-Associated Protein 1 (YAP1) Correlates with Metastasis in Patients with Breast Cancer

10.21203/rs.3.rs-77394/v1 ◽

2020 ◽

Author(s):

Yoon Jin Cha ◽

Soong June Bae ◽

Dooreh Kim ◽

Sung Gwe Ahn ◽

Joon Jeong ◽

...

Keyword(s):

Breast Cancer ◽

Hippo Pathway ◽

External Validation ◽

Free Survival ◽

Severance Hospital ◽

Aggressive Tumor ◽

The Hippo Pathway ◽

The Impact ◽

Different Levels

Abstract Background: Yes-associated protein 1 (YAP1) is a transcription factor regulated by the Hippo pathway and functions as an oncogene in various solid tumors under dysregulated Hippo pathway. However, the role of YAP1 in breast cancer is controversial. Here, we investigated the impact of different levels of nuclear YAP1 expression on the clinical characteristics and survival outcome of patients with breast cancer.Patients and Methods: Retrospectively obtained 469 breast tumor samples at the Gangnam Severance Hospital were examined for YAP1 expression by immunohistochemistry, and the clinical data were analyzed. External validation was performed using a retrospective cohort and tissues in 489 patients from Severance Hospital.Results: High nuclear YAP1 expression was associated with hormone receptor negativity and aggressive tumor behavior, including lymph node metastasis, high Ki67 labeling index and inferior distant metastasis-free survival (DMFS), and also confirmed in external validation cohort. In patients with triple-negative breast cancer (TNBC), high nuclear YAP1 expression was an independent significant determinant of poor DMFS (HR 1.947, 95% CIs 1.003-3.779, P=0.049).Conclusion: Our findings suggest that nuclear YAP1 expression is a biomarker of adverse prognosis and a potential therapeutic target in patients with breast cancer, especially in TNBC.

Download Full-text

Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

Frontiers in Oncology ◽

10.3389/fonc.2021.626309 ◽

2021 ◽

Vol 11 ◽

Author(s):

Malina Xiao ◽

Alice Benoit ◽

Meriem Hasmim ◽

Caroline Duhem ◽

Guillaume Vogin ◽

...

Keyword(s):

Clinical Trials ◽

Current Knowledge ◽

Therapeutic Benefit ◽

Cancer Therapies ◽

Cancer Resistance ◽

Tumor Resistance ◽

Anti Cancer ◽

Almost All ◽

The Impact

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

Download Full-text

The impact of autophagy during the development and survival of glioblastoma

Open Biology ◽

10.1098/rsob.200184 ◽

2020 ◽

Vol 10 (9) ◽

pp. 200184

Author(s):

Joanne E. Simpson ◽

Noor Gammoh

Keyword(s):

Tyrosine Kinases ◽

Tumour Growth ◽

Treatment Options ◽

Adult Brain ◽

Cancer Models ◽

Anti Cancer ◽

Genomic Studies ◽

Cellular Components ◽

The Impact

Glioblastoma is the most common and aggressive adult brain tumour, with poor median survival and limited treatment options. Following surgical resection and chemotherapy, recurrence of the disease is inevitable. Genomic studies have identified key drivers of glioblastoma development, including amplifications of receptor tyrosine kinases, which drive tumour growth. To improve treatment, it is crucial to understand survival response processes in glioblastoma that fuel cell proliferation and promote resistance to treatment. One such process is autophagy, a catabolic pathway that delivers cellular components sequestered into vesicles for lysosomal degradation. Autophagy plays an important role in maintaining cellular homeostasis and is upregulated during stress conditions, such as limited nutrient and oxygen availability, and in response to anti-cancer therapy. Autophagy can also regulate pro-growth signalling and metabolic rewiring of cancer cells in order to support tumour growth. In this review, we will discuss our current understanding of how autophagy is implicated in glioblastoma development and survival. When appropriate, we will refer to findings derived from the role of autophagy in other cancer models and predict the outcome of manipulating autophagy during glioblastoma treatment.

Download Full-text