Insurgent micrometastases: Sleeper cells and harboring the enemy

Wieder, Robert

doi:10.1002/jso.20199

Cited by 22 publications

(20 citation statements)

References 36 publications

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“…Given the stimulation of fibronectin adhesiveness following oncogenic ERBB2 signaling, we also examined the influence of this interaction on tumor cell chemoresistance and found that fibronectin ligation lead to a 5-fold increase in resistance against drugs used in breast cancer chemotherapy protocols (5-FU and CDDP), further supporting the clinical relevance of the ERBB2/a5 integrin regulatory interaction. One hallmark of tumor cell dormancy is the inherent resistance of nondividing cells against chemotherapeutic agents (26,55,71). As suggested by the work of Korah et al (24), as well as by our functional in vitro studies, the a5h1 integrin/fibronectin interaction may be a (perhaps essential) marker for dormant cells, and therefore a very interesting target for breast cancer therapy.…”

Section: Discussionmentioning

confidence: 58%

“…25, 26, 54-56 for reviews). Metastatic growth of tumor cells at distant sites is generally considered a late step during tumorigenesis, but current metastasis models hypothesize that dissemination of single tumor cells begins even in the very early phases of malignancy (25,26,57). Such disseminated micrometastases can be found in a number of organs, like the bone marrow, as solitary cells, where they may survive for a long period of time, eventually leading to metastatic disease even decades later.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a5h1 integrin fibronectin receptor ligation is the key mediator of cell survival in an in vitro bone marrow metastasis model in which breast carcinoma cells undergo a transition to a nonproliferative, dormant state in response to fibroblast growth factor 2 (FGF2) treatment (24). For patients with breast cancer, the presence of single dormant cells in their bone marrow is indicative of fatal relapse including metastatic disease in bone, and ERBB2 has been implicated in the survival of such disseminated cells (25,26).…”

Section: Introductionmentioning

confidence: 99%

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ERBB2-Mediated Transcriptional Up-regulation of the α5β1 Integrin Fibronectin Receptor Promotes Tumor Cell Survival Under Adverse Conditions

et al. 2006

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Oncogenic activation of the receptor tyrosine kinase ERBB2 is a key event in the development of a number of epithelial malignancies. In these tumors, high levels of ERBB2 are strongly associated with metastatic disease and poor prognosis. Paradoxically, an inherent cellular response to hypermitogenic signaling by ERBB2 and other oncogenes seems to be growth arrest, rather than proliferation. Molecular characterization of this yet undefined antiproliferative state in independent cell lines overexpressing either wild-type ERBB2 or the mutationally activated receptor unveiled a dramatic induction of the A5B1 integrin fibronectin receptor. A5 Integrin up-regulation is mainly a transcriptional response mediated by the hypoxia-inducible transcription factors (HIF), leading to a massive increase in membrane-resident receptor molecules and enhanced fibronectin adhesiveness of the respective cells. Functionally, ERBB2-dependent ligation of fibronectin results in improved survival of mammary adenocarcinoma cells under adverse conditions, like serum withdrawal, hypoxia, and chemotherapy. HIF-1A is an independent predictor of poor overall survival in patients with breast cancer. In particular, HIF-1A overexpression correlates significantly with early local relapse and distant metastasis, a phenotype also highly characteristic of ERBB2-positive tumors. As HIF-1A is known to be stabilized by ERBB2 signaling under normoxic conditions, we propose that A5 integrin is a major effector in this regulatory circuit and may represent the molecular basis for the HIF-1A-dependent aggressiveness observed in ERBB2-overexpressing breast carcinomas. Hypermitogenic ERBB2 signaling and tumor hypoxia may act synergistically to favor the establishment of chemoresistant dormant micrometastatic cells frequently observed in patients with breast cancer. This new insight could be the basis for additional approaches complementing current cancer therapy. (Cancer Res 2006; 66(7): 3715-25)

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ERBB2-Mediated Transcriptional Up-regulation of the α5β1 Integrin Fibronectin Receptor Promotes Tumor Cell Survival Under Adverse Conditions

et al. 2006

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“…With the confirmation of autophagy in hepatoma SMMC-7721 and HepG2 cells under hypoxia, its relation with chemoresistance deserves our attention. We therefore examined the effect of 3-MA, an inhibitor of autophagy, 49,50 on the occurrence of The resistance of cancer cells to radiation or chemotherapy may be partially due to the induction of HIF-1α and activation of HIF-1. 58-60 HIF-1, by regulating the expression of its target downstream BNIP3 and BNIP3L, regulates the autophagy under hypoxia.…”

Section: -5mentioning

confidence: 99%

Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells

Song¹,

Qu²,

Guo³

et al. 2009

Autophagy

171

131

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“…1), is greatly diminished and most patients die relatively rapidly from progressive disease. 2 Even in the absence of clinically or pathologically overt metastases at diagnosis, patients often develop metastatic disease, leading to the concept of micro-metastases that are too small to be detected by current diagnostic technologies. 3,4 Therefore, patients are often given adjuvant therapy after curative surgery to minimize the risk of loco-regional recurrence as well as metastatic disease.…”

Section: Introductionmentioning

confidence: 99%