The common mutation
in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) ...and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15-20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).
Molecular Biology of Osteosarcoma Czarnecka, Anna M; Synoradzki, Kamil; Firlej, Wiktoria ...
Cancers,
07/2020, Volume:
12, Issue:
8
Journal Article
Peer reviewed
Open access
Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that ...predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond-Blackfan anemia.
is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK-ERK pathways. Several genomic studies showed frequent alterations in the
gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in
,
,
,
,
,
,
and
genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.
The introduction of anti-angiogenic drugs especially tyrosine kinase inhibitors (TKIs) was a breakthrough in the treatment of renal cell carcinoma (RCC). Although TKIs have significantly improved ...outcome in patients with metastatic disease, the majority still develop resistance over time. Because different combinations and sequences of TKIs are tested in clinical trials, resistance patterns and mechanisms underlying this phenomenon should be thoroughly investigated. From a clinical point of view, resistance occurs either as a primary phenomenon (intrinsic) or as a secondary phenomenon related to various escape/evasive mechanisms that the tumor develops in response to vascular endothelial growth factor (VEGF) inhibition. Intrinsic resistance is less common, and related to the primary redundancy of available angiogenic signals from the tumor, causing unresponsiveness to VEGF-targeted therapies. Acquired resistance in tumors is associated with activation of an angiogenic switch which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Multiple mechanisms can be involved in different tumor settings that contribute both to evasive and intrinsic resistance, and current endeavor aims to identify these processes and assess their importance in clinical settings and design of pharmacological strategies that lead to enduring anti-angiogenic therapies.
Descriptions of somatic cell divisions were made as early as the eighteenth and nineteenth centuries with varying degrees of accuracy. In this paper, we would like to present a forgotten Polish ...scientist Waclaw Mayzel (1847–1916), who described somatic mitosis in the corneal epithelium of the frog in 1875 almost simultaneously with the recognized discoveries of animal mitosis by Otto Bütschli and plant mitosis by Eduard Strasburger.
In the field of cancer research, scientific investigations are based on analysing differences in the secretome, the proteome, the transcriptome, the expression of cell surface molecules, and the ...deregulation of signal transduction pathways between neoplastic and normal cells. Accumulating evidence indicates a crucial role in carcinogenesis concerning not only stromal cells but also normal cells from target organs and tissue where tumours emerge. The tumour microenvironment (TME) definitively plays an important role in regulating neighbouring cell behaviour. To date, limited attention has been focused upon interactions between cancer cells and normal cells. This review concentrates on the interactions between stromal and healthy cells from the TME in cancer development. In the article, the authors also describe mutations, genes and proteins expression pattern that are involved in tumour development in target organ.
The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in ...patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with TP53 dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future.
Soft tissue sarcomas (STS) originating from connective tissue rarely affect the lymph nodes. However, involvement of lymph nodes in STS is an important aspect of prognosis and treatment. Currently, ...there is no consensus on the diagnosis and management of lymph node metastases in STS. The key risk factor for nodal involvement is the histological subtype of sarcoma. Radiological and pathological evaluation seems to be the most effective method of assessing lymph nodes in these neoplasms. Thus, sentinel lymph node biopsy (SLNB), which has been shown to be valuable in the management of melanoma or breast cancer, may also be a beneficial diagnostic option in some high-risk STS subtypes. This review summarizes data on the risk factors and clinical characteristics of lymph node involvement in STS. Possible management and therapeutic options are also discussed.
Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several ...advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is growing continuously. We may consider radiotherapy, chemotherapy, targeted therapy, radiosensitizers, hyperthermia, and their combinations. This review discusses possible neoadjuvant treatment options in STS with an emphasis on available evidence, indications for each treatment type, and related risks. Finally, we summarize current recommendations of the STS neoadjuvant therapy response assessment.
The aim of this study was to investigate the prognostic impact of baseline tumor burden and loci on the efficacy of first line renal cancer treatment with sunitinib. Baseline and on-treatment CT ...scans were evaluated. Both the Kaplan-Meier and Weibull modelling survival estimators have been used to describe sunitinib treatment response. Logistic regression was used to confirm associations between tumor site, burden and survival. Additionally, analysis of the metastases co-occurrence was conducted using the Bayesian inference on treated and external validation cohorts. 100 patients with metastatic clear cell renal cell carcinoma were treated with sunitinib in this study. Presence of metastases in the abdominal region (HR = 3.93), and the number of brain metastases correlate with shorter PFS, while the presence of thoracic metastases (HR = 0.47) with longer PFS. Localization of metastases in the abdominal region significantly impacts risk of metastases development in other locations including bone and brain metastases. Biology of metastases, in particular their localization, requires further molecular and clinical investigation.
The
cancer stem cell
(
CSC
) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are ...indifferently understood; however, the first and most thoroughly investigated are CD105-positive
CSCs
. The article presents a detailed comparison of all renal
CSC
-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function,
clear-cell
RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal
CSC
-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal
CSCs
and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
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