We are witnessing several revolutionary technological advances in cancer. These innovations have not only contributed to a growing understanding of the tumor and its microenvironment but also ...uncovered an increasing array of new therapeutic targets. For most advanced cancers, therapy resistance limits the benefit of single-agent therapies. Therefore, some 5,000 clinical trials are ongoing globally to probe the clinical benefit of new combination treatments. However, the possibilities to combine individual treatments dramatically outnumber the patients available to enroll in clinical trials. This comes at a potential cost of missed opportunities, clinical failure, avoidable toxicity, insufficient patient accrual, and financial loss. A solution may be to design combination therapies more rationally, which are informed by fundamental biological and mechanistic insight. We will discuss some successes and failures of current treatment combinations, as well as interesting emerging preclinical concepts that warrant clinical exploration.
Boshuizen and Peeper address the conundrum that, whereas for most advanced cancers combination therapies are required for durable responses, the possible combinations dramatically outnumber the patients to be enrolled in clinical studies. They argue that there is an opportunity to take advantage of both technological advances and fundamental mechanistic insight to design combination treatments in a more rational fashion.
Oncogene-induced cellular senescence constitutes a strong anti-proliferative response, which can be set in motion following either oncogene activation or loss of tumour suppressor signalling. It ...serves to limit the expansion of early neoplastic cells and as such is a potent cancer-protective response to oncogenic events. Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment. How are such signals integrated into a coordinated response and what are the implications of this unexpected finding?
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
3.
The essence of senescence Kuilman, Thomas; Michaloglou, Chrysiis; Mooi, Wolter J ...
Genes & development,
2010-Nov-15, 20101115, Letnik:
24, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of "cellular senescence" ...in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo.
Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably ...develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape route. By switching from a proliferative to an invasive state, melanoma cells can acquire resistance to these targeted therapeutics. Interestingly, phenotype switching bears a striking resemblance to the epithelial-to-mesenchymal-like transition that has been described to occur in cancer stem cells in other tumor types. We propose that these changes are manifestations of one and the same underlying feature, namely a dynamic and reversible phenotypic tumor cell plasticity that renders a proportion of cells both more invasive and resistant to therapy. At the same time, the specific characteristics of these tumor cell populations offer potential for being explored as target for therapeutic intervention.
In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body ...of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
6.
Metastasis mechanisms Geiger, Thomas R.; Peeper, Daniel S.
Biochimica et biophysica acta,
December 2009, 2009-Dec, 2009-12-00, Letnik:
1796, Številka:
2
Journal Article
Recenzirano
Metastasis, the spread of malignant cells from a primary tumor to distant sites, poses the biggest problem to cancer treatment and is the main cause of death of cancer patients. It occurs in a series ...of discrete steps, which have been modeled into a “metastatic cascade”. In this review, we comprehensively describe the molecular and cellular mechanisms underlying the different steps, including Epithelial–Mesenchymal Transition (EMT), invasion, anoikis, angiogenesis, transport through vessels and outgrowth of secondary tumors. Furthermore, we implement recent findings that have broadened and challenged the classical view on the metastatic cascade, for example the establishment of a “premetastatic niche”, the requirement of stem cell-like properties, the role of the tumor stroma and paracrine interactions of the tumor with cells in distant anatomical sites. A better understanding of the molecular processes underlying metastasis will conceivably present us with novel targets for therapeutic intervention.
Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using ...patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.
Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is ...associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using ...combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBPβ cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16
INK4A-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer.
Cellular senescence is characterized by a largely irreversible cell cycle arrest that can be triggered by many types of intrinsic and extrinsic stress. These include telomere malfunction, oncogene ...activation and tumor suppressor gene inactivation. Ultimately, such events culminate in the activation of a tumor suppressor gene network. Since the first description of Oncogene-Induced cellular Senescence (OIS) little over a decade ago, many subsequent studies have confirmed that OIS prevents cells from undergoing oncogenic transformation in vitro . However, it has long been debated whether any in vivo correlates exist. It is only since recent years that evidence has been accumulating indicating that OIS in vivo does correspond to a major protective mechanism against cancer. In this review, we highlight some of the recent developments.
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