From differential analysis for the identification of biomarkers, to functional analysis for the evidencing of new therapeutic targets, proteomics brings new comprehensive information for a better ...understanding of the molecular basis of oncology and new perspectives for the clinic. However the major limitation of proteomic investigations and more generally of post-genomic approaches remains the molecular and cellular complexity of biological systems. This will be illustrated with the case of breast cancer.
Aims
Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally ...advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial.
Methods
Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer‐specific mortality and all‐cause mortality.
Results
PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow‐up interval of the study (log‐rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05–1.92, P = 0.021).
Conclusions
The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow‐up.
De l'approche différentielle pour l'identification de marqueurs à l'analyse fonctionnelle pour la mise en évidence de cibles thérapeutiques, la protéomique apporte de nouvelles données fondamentales ...pour la compréhension des mécanismes de la cancérogenèse et des perspectives pour la clinique. Néanmoins la protéomique, comme l'ensemble des approches de post-génomique, doit faire face à la complexité cellulaire et moléculaire des systèmes biologiques ; le cas du cancer du sein illustre bien cette situation.
From differential analysis for the identification of biomarkers, to functional analysis for the evidencing of new therapeutic targets, proteomics brings new comprehensive information for a better understanding of the molecular basis of oncology and new perspectives for the clinic. However the major limitation of proteomic investigations and more generally of post-genomic approaches remains the molecular and cellular complexity of biological systems. This will be illustrated with the case of breast cancer.
The imprinted H19 gene has riboregulatory functions. We show here that H19 transcription is up-regulated during the S-phase of growth-stimulated cells and that the H19 promoter is activated by E2F1 ...in breast cancer cells. H19 repression by pRb and E2F6 confirms the E2F1-dependent control of the H19 promoter. Consistently, we demonstrate by chromatin immunoprecipitation assays that endogenous E2F1 is recruited to the H19 promoter in vivo . The functionality of E2F promoter sites was further confirmed by gel shift and mutagenesis experiments, revealing that these
sites are required for binding and promoter response to E2F1 exogenous expression and serum stimulation. Furthermore, we show
that H19 overexpression confers a growth advantage on breast cancer cells released from growth arrest as well as in asynchronously
growing cells. The H19 knockdown by small interfering RNA duplexes impedes S-phase entry in both wild-type and stably H19 -transfected cells. Based on these findings, we conclude that the H19 RNA is actively linked to E2F1 to promote cell cycle progression of breast cancer cells. This clearly supports the H19 oncogenic function in breast tumor genesis.
This Commentary illustrates that the pathological involvement of nerve growth factor in psoriasis is related not only to its effects on keratinocyte proliferation and inflammation but also to its ...neurotrophic activity.
The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer ...neuroscience for malignancies arising outside of the central nervous system.
The near completion of human genome sequencing and the introduction of mass spectrometry combined with advanced bioinformatics for protein identification have led to the emergence of proteomics as a ...powerful tool for characterizing new markers and therapeutic targets. Breast cancer proteomics has already identified proteins of potential clinical interest, such as the molecular chaperone 14-3-3 sigma and the heat shock protein HSP90, and technological innovations such as large scale and high throughput analysis are now driving the field. Methods in functional proteomics have also been developed to study the intracellular signaling pathways that underlie the development of breast cancer cells. As illustrated by fibroblast growth factor-2 and the H19 noncoding oncogenic mRNA, proteomics is a pertinent approach to identify signaling proteins and to decipher the complex signaling circuitry involved in tumor growth and metastasis. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast carcinogenesis and to identify new therapeutic targets. The next challenge will be the introduction of proteomics as a tool for the clinic, for the establishment of diagnosis, prognosis, and the monitoring of treatment; however, this ambitious goal still requires further technological progress in the field.
We show here that nerve growth factor (NGF), the canonical neurotrophic factor, is synthesized and released by breast cancer cells. High levels of NGF transcript and protein were detected in breast ...cancer cells by reverse transcription-PCR, Western blotting, ELISA assay and immunohistochemistry. Conversely, NGF production could not be detected in normal breast epithelial cells at either the transcriptional or protein level. Confocal analysis indicated the presence of NGF within classical secretion vesicles. Breast cancer cell-produced NGF was biologically active, as demonstrated by its ability to induce the neuronal differentiation of embryonic neural precursor cells. Importantly, the constitutive growth of breast cancer cells was strongly inhibited by either NGF-neutralizing antibodies or K-252a, a pharmacological inhibitor of NGF receptor TrkA, indicating the existence of an NGF autocrine loop. Together, our data demonstrate the physiological relevance of NGF in breast cancer and its potential interest as a marker and therapeutic target.
Nerve growth factor (NGF) has long been known for its effects on neuronal cell survival and differentiation. This prototypical neurotrophic factor stimulates neurons through two distinct classes of ...membrane receptors: the TrkA tyrosine kinase receptor, and the tumor necrosis factor receptor family member p75NTR, also known as the common neurotrophin receptor. Somewhat surprisingly, there is a growing body of evidence indicating that NGF is also a major stimulator of breast cancer cell growth. Both the survival and proliferation of breast cancer cells are strongly stimulated by NGF, mediated by TrkA and p75NTR respectively, utilising signaling pathways similar to those described for neurons. In addition, although NGF is produced by breast cancer cells, it is not in normal breast epithelial cells, giving rise to an autocrine stimulation of tumor growth. Therefore, NGF receptors and signaling are thus looking increasingly promising as potential drug targets for breast cancer.
The common neurotrophin receptor p75NTRhas been shown to initiate intracellular signaling that leads either to cell survival or to apoptosis depending on the cell type examined; however, the ...mechanism by which p75NTR initiates its intracellular transduction remains unclear. We show here that the tumor necrosis factor receptor-associated death domain protein (TRADD) interacts with p75NTR upon nerve growth factor (NGF) stimulation. TRADD could be immunodetected after p75NTRimmunoprecipitation from MCF-7 breast cancer cells stimulated by nerve growth factor. In addition, confocal microscopy indicated that NGF stimulation induced the plasma membrane localization of TRADD. Using a dominant negative form of TRADD, we also show that interactions between p75NTR and TRADD are dependent on the death domain of TRADD, thus demonstrating its requirement for binding. Furthermore, the p75NTR-mediated activation of NF-κB was inhibited by transfection with a dominant negative TRADD, resulting in an inhibition of NGF antiapoptotic activity. These results thus demonstrate that TRADD is involved in the p75NTR-mediated antiapoptotic activity of NGF in breast cancer cells.
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