Epithelial Cell Dissemination and Readhesion: Analysis of Factors Contributing to Metastasis Formation in Breast Cancer

Hekimian, Katya; Meisezahl, Sandra; Trompelt, Kristin; Rabenstein, C.; Pachmann, Katharina

doi:10.5402/2012/601810

Cited by 19 publications

(17 citation statements)

References 26 publications

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“…Even newer targeted tumor-specific small-molecule inhibitors or antibody therapies may be ineffective on CTCs if the CTCs are molecularly different from the primary tumor cells as a result of newly acquired mutations or selective dissemination of clonally heterogeneous tumor cells [23]. For example, microtubule-targeting cytotoxic chemotherapies such as taxanes, which are extremely effective in their anti-proliferative effects on the primary tumor, can significantly increase CTCs in the patients' blood when given prior to surgery [49]. Accumulating evidence on the role of CTCs in promoting metastasis [22-24] highlights the necessity of screening developing chemotherapeutics for their effects on free-floating suspended cells in addition to adherent cell conditions to avoid inadvertently increasing CTCs and metastatic risk.…”

Section: Discussionmentioning

confidence: 99%

ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

et al. 2015

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The presence of circulating tumor cells (CTCs) in blood predicts poor patient outcome and CTC frequency is correlated with higher risk of metastasis. Recently discovered, novel microtubule-based structures, microtentacles, can enhance reattachment of CTCs to the vasculature. Microtentacles are highly dynamic membrane protrusions formed in detached cells and occur when physical forces generated by the outwardly expanding microtubules overcome the contractile force of the actin cortex. Rho-associated kinase (ROCK) is a major regulator of actomyosin contractility and Rho/ROCK over-activation is implicated in tumor metastasis. ROCK inhibitors are gaining popularity as potential cancer therapeutics based on their success in reducing adherent tumor cell migration and invasion. However, the effect of ROCK inhibition on detached cells in circulation is largely unknown. In this study, we use breast tumor cells in suspension to mimic detached CTCs and show that destabilizing the actin cortex through ROCK inhibition in suspended cells promotes the formation of microtentacles and enhances reattachment of cells from suspension. Conversely, increasing actomyosin contraction by Rho over-activation reduces microtentacle frequency and reattachment. Although ROCK inhibitors may be effective in reducing adherent tumor cell behavior, our results indicate that they could inadvertently increase metastatic potential of non-adherent CTCs by increasing their reattachment efficacy.

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Section: Discussionmentioning

confidence: 99%

ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

et al. 2015

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“…However, Tau also promotes microtentacles and tumor cell lung retention that could account for enrichment of Tau in metastatic tumors(29). Careful monitoring shows that CTCs in breast cancer patients can increase up to 1000-fold during neoadjuvant taxane treatment and that patients with increasing CTC levels have a 25-fold higher recurrence risk(35). Since the current detection limit for clinical imaging is a tumor foci of approximately 10 million cells(36), it will be important to develop methods that are capable of distinguishing whether primary tumor shrinkage during neoadjuvant therapy is occurring due to tumor cell death or tumor cell scattering.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: New Signaling Considerations When Targeting Cytoskeletal Balance to Reduce Tumor Growth

Chakrabarti

Hessler

Bhandary

et al. 2015

Clinical Cancer Research

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The dynamic balance between microtubule extension and actin contraction regulates mammalian cell shape, division and motility, which has made the cytoskeleton an attractive and very successful target for cancer drugs. Numerous compounds in clinical use to reduce tumor growth cause microtubule breakdown (Vinca alkaloids, Colchicine-site, Halichodrins) or hyperstabilization of microtubules (Taxanes, Epothilones). However, both of these strategies indiscriminately alter the assembly and dynamics of all microtubules, which causes significant dose-limiting toxicities on normal tissues. Emerging data is revealing that posttranslational modifications of tubulin (detyrosination, acetylation) or microtubule-associated proteins (Tau, Aurora kinase) may allow for more specific targeting of microtubule subsets, thereby avoiding the broad disruption of all microtubule polymerization. Developing approaches to reduce tumor cell migration and invasion focus on disrupting actin regulation by the kinases SRC and ROCK. Since the dynamic balance between microtubule extension and actin contraction also regulates cell fate decisions and stem cell characteristics, disrupting this cytoskeletal balance could yield unexpected effects beyond tumor growth. This review will examine recent data demonstrating that cytoskeletal cancer drugs affect wound healing responses, microtentacle-dependent reattachment efficiency and stem cell characteristics in ways that could impact the metastatic potential of tumor cells, both beneficially and detrimentally.

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“…Once detached, these CTCs undergo a variety of changes, both molecularly and structurally, to adapt to the new microenvironment. After detachment and survival in the circulation, CTCs must re-attach and arrest at a secondary site [ 15 , 16 ]. Tumor cell re-attachment is a process dependent on stable microtubules [ 17 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment

et al. 2015

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The presence of tumor cells in the circulation is associated with a higher risk of metastasis in patients with breast cancer. Circulating breast tumor cells use tubulin-based structures known as microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. AMP-activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We report that AMPK can regulate the cytoskeleton of breast cancer cells in both attached and suspended conditions. We tested the effects of AMPK on microtubule stability and the actin-severing protein, cofilin. AMPK inhibition with compound c increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation with A-769662 decreased microtubule stability and cofilin activation with concurrent decreases in McTN formation and cell re-attachment. This data shows for the first time that AMPK shifts the balance of cytoskeletal forces in suspended breast cancer cells, which affect their ability to form McTNs and re-attach. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of breast tumor cells.

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Epithelial Cell Dissemination and Readhesion: Analysis of Factors Contributing to Metastasis Formation in Breast Cancer

Cited by 19 publications

References 26 publications

ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

Molecular Pathways: New Signaling Considerations When Targeting Cytoskeletal Balance to Reduce Tumor Growth

Pharmacologic regulation of AMPK in breast cancer affects cytoskeletal properties involved with microtentacle formation and re-attachment

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