The cancer's nervous tooth: Considering the neuronal crosstalk within tumors

Entschladen, Frank; Palm, Daniel; Niggemann, Bernd; Zaenker, Kurt S.

doi:10.1016/j.semcancer.2007.12.004

Cited by 49 publications

(43 citation statements)

References 31 publications

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“…In support of this, BDNF activation of TrkB has been found to induce vascular endothelial growth factor (VEGF) expression via hypoxia inducible factor-1-alpha (HIF-1-α) in neuroblastoma cells [47]. It has also been suggested that increased expression of TrkB/BDNF may indicate increased neo-neurogenesis, where tumors initiate their own innervation by releasing neurotrophic factors [48]. This may further support tumour progression by the release of neurotransmitters which enhance metastasis.…”

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

2011

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IntroductionBrain-derived neurotrophic factor (BDNF) has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC). However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period.MethodsBC tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI) and clinical outcome over a 10 year follow-up period.ResultsImmuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007). The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009). Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047). Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR) (p = 0.0014), death from BC (p = 0.018) and poor prognosis overall (p = 0.013). After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS) (106 vs. 136 months, p = 0.006). BDNF emerged as an independent prognostic variable in multivariate analysis for disease free survival (DFS) (p = 0.026) and approached significance for OS (p = 0.055).ConclusionBDNF expression was found to be significantly higher in BC specimens compared to normal tissue. Higher transcript levels were significantly associated with unfavourable pathological parameters including nodal positivity and increasing NPI; and adverse clinical outcomes including LR, death from BC, poor prognosis, reduced DFS and OS. BDNF offers utility as a prognostic marker and potential for targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

2011

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“…Research from the past 10 years uncovered several crucial features of nerve-cancer interactions in PCa, including neural plasticity, neural invasion (NI), and the associated neuropathic pain syndrome in PCa (Ceyhan et al, 2009a; Demir et al, 2010a). Just like increased appreciation of the role of the members of tumor stroma, neural cells are increasingly perceived as major modulators of tumor growth and spread (Entschladen et al, 2008). The present review aims at providing an overview of the so far elucidated interactions of intrapancreatic nerves with PCa cells and with other members of the pancreatic tumor stroma and raises several important questions related to these exciting interactions.…”

Section: Introductionmentioning

confidence: 99%

Nerve-cancer interactions in the stromal biology of pancreatic cancer

2012

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Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.

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“…We have reported previously that PC-3 prostate carcinoma cells have influence on the SH-SY5Y neuroblastoma cells with regard to their differentiation by the release of signal substances [16]. However, we have in this previous work focussed on the expression of some neuronal growth factors.…”

Section: Resultsmentioning

confidence: 99%

PC-3 prostate carcinoma cells release signal substances that influence the migratory activity of cells in the tumor's microenvironment

et al. 2010

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BackgroundTumor cells interact with the cells of the microenvironment not only by cell-cell-contacts but also by the release of signal substances. These substances are known to induce tumor vascularization, especially under hypoxic conditions, but are also supposed to provoke other processes such as tumor innervation and inflammatory conditions. Inflammation is mediated by two organ systems, the neuroendocrine system and the immune system. Therefore, we investigated the influence of substances released by PC-3 human prostate carcinoma cells on SH-SY5Y neuroblastoma cells as well as neutrophil granulocytes and cytotoxic T lymphocytes, especially with regard to their migratory activity.ResultsPC-3 cells express several cytokines and growth factors including vascular endothelial growth factors, fibroblast growth factors, interleukins and neurotrophic factors. SH-SY5Y cells are impaired in their migratory activity by PC-3 cell culture supernatant, but orientate chemotactically towards the source. Neutrophil granulocytes increase their locomotory activity only in response to cell culture supernantant of hypoxic but not of normoxic PC-3 cells. In contrast, cytotoxic T lymphocytes do not change their migratory activity in response to either culture supernatant, but increase their cytotoxicity, whereas supernatant of normoxic PC-3 cells leads to a stronger increase than that of hypoxic PC-3 cells.ConclusionsPC-3 cells release several signal substances that influence the behavior of the cells in the tumor's microenvironment, whereas no clear pattern towards proinflammatory or immunosuppressive conditions can be seen.

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The cancer's nervous tooth: Considering the neuronal crosstalk within tumors

Cited by 49 publications

References 31 publications

Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

Nerve-cancer interactions in the stromal biology of pancreatic cancer

PC-3 prostate carcinoma cells release signal substances that influence the migratory activity of cells in the tumor's microenvironment

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