Metastasis: Tumor cells becoming MENAcing

Department of Biology and Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT), 77 Massachusetts Ave, Cambridge, MA 02138, USA.
Trends in cell biology (Impact Factor: 12.01). 11/2010; 21(2):81-90. DOI: 10.1016/j.tcb.2010.10.001
Source: PubMed


During breast cancer metastasis cells emigrate from the primary tumor to the bloodstream, and this carries them to distant sites where they infiltrate and sometimes form metastases within target organs. These cells must penetrate the dense extracellular matrix comprising the basement membrane of the mammary duct/acinus and migrate toward blood and lymphatic vessels, processes that mammary tumor cells execute primarily using epidermal growth factor (EGF)-dependent protrusive and migratory activity. Here, we focus on how the actin regulatory protein Mena affects EGF-elicited movement, invasion and metastasis. Recent findings indicate that, in invasive migratory tumor cells, Mena isoforms that endow heightened sensitivity to EGF and increased protrusive and migratory abilities are upregulated, whereas other isoforms are selectively downregulated. This change in Mena isoform expression enables tumor cells to invade in response to otherwise benign EGF stimulus levels and could offer an opportunity to identify metastatic risk in patients.

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    • "MenaINV, (originally termed Mena+++), expression confers a potent pro-metastatic phenotype when expressed in breast cancer cells by potentiating their chemotactic response to epidermal growth factor (EGF), thereby enhancing their ability to engage in efficient streaming motility via increasing their paracrine signaling with macrophages [3,13,14]. The Mena11a, a non-metastatic isoform, contains an alternately-included exon encoding a 21 amino acid insertion located in the carboxy-terminal [7]. Consistent with its down-regulation during tumor progression in vivo [11,15], Mena11a is expressed in epithelial-like but not mesenchymal-like tumor cell lines [16], and is down-regulated when human mammary epithelial cells undergo epithelial to mesenchymal transition (EMT) [12]. "
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    ABSTRACT: Introduction Mena, an Ena/VASP protein family member, is a key actin regulatory protein. Mena is up-regulated in breast cancers and promotes invasion and motility of tumor cells. Mena has multiple splice variants, including Mena invasive (MenaINV) and Mena11a, which are expressed in invasive or non-invasive tumor cells, respectively. We developed a multiplex quantitative immunofluorescence (MQIF) approach to assess the fraction of Mena lacking 11a sequence as a method to infer the presence of invasive tumor cells represented as total Mena minus Mena11a (called Menacalc) and determined its association with metastasis in breast cancer. Methods The MQIF method was applied to two independent primary breast cancer cohorts (Cohort 1 with 501 and Cohort 2 with 296 patients) using antibodies against Mena and its isoform, Mena11a. Menacalc was determined for each patient and assessed for association with risk of disease-specific death. Results Total Mena or Mena11a isoform expression failed to show any statistically significant association with outcome in either cohort. However, assessment of Menacalc showed that relatively high levels of this biomarker is associated with poor outcome in two independent breast cancer cohorts (log rank P = 0.0004 for Cohort 1 and 0.0321 for Cohort 2). Multivariate analysis on combined cohorts revealed that high Menacalc is associated with poor outcome, independent of age, node status, receptor status and tumor size. Conclusions High Menacalc levels identify a subgroup of breast cancer patients with poor disease-specific survival, suggesting that Menacalc may serve as a biomarker for metastasis.
    Breast cancer research: BCR 09/2012; 14(5):R124. DOI:10.1186/bcr3318 · 5.49 Impact Factor
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    • "Previous studies have established a link between the migratory properties of cancer cells and their invasive and metastatic potential (Clarke et al, 2009). Cancer cells respond to cues from the extracellular environment in the regulation of various functions including motility (Gertler and Condeelis, 2011). These stimuli include stroma, growth factors, cytokines, matrix metalloproteases (MMPs) and ECM proteins (Briest et al, 2012). "
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    ABSTRACT: Activation of Akt and increased expression of integrin β(3) are the two most important changes that have been linked to the attainment of metastatic potential by prostate cancer cells. However, a direct link between Akt activity and inside-out activation of integrin β(3) in mediating prostate cancer cell metastatic properties is not established. Using functional and biochemical approaches, we examined the role of Akt1 in the affinity modulation of integrin β(3) in prostate cancer cells. Although expression of murine TRAMP and human PC3 cells with constitutively active Akt1 (CA-Akt1) enhanced their affinity for integrin α(v)β(3) specific ligands and motility on various extracellular matrix proteins, the reverse was observed with the expression of dominant-negative Akt1 (DN-Akt1). Although enhanced motility and transendothelial migration of CA-Akt1-expressing cells were blunted by co-expression with DN-integrin β(3) or upon pre-treatment with integrin β(3)-blocking antibodies (LM 609), impaired motility and transendothelial migration of DN-Akt1-expressing cells were rescued by pre-treatment of prostate cancer cells with integrin β(3)-activating antibodies, AP7.4. Our data is the first to demonstrate a link between Akt1 activity and affinity modulation of integrin β(3) in the regulation of prostate cancer cell motility, transendothelial migration and chemotaxis to metastatic stimuli.
    British Journal of Cancer 07/2012; 107(4):713-23. DOI:10.1038/bjc.2012.295 · 4.84 Impact Factor
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    • "is supported by in vivo imaging of mammary tumors, which demonstrates the following regarding motile tumor cells: they represent only a small percentage of tumor cells, they are distributed throughout the tumor, and they are found most commonly localized to precise areas within the tumor [5]. Furthermore, genes associated with metastasis are expressed early and are found in tumor cells throughout the tumor [2]. Also in support of the model is the observation that micrometastases are commonly genetically heterogeneous, indicating that the invasiveness and migration are not limited to stable gene alterations. "
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    ABSTRACT: Despite diagnostic advances, breast cancer remains the most prevalent cancer among women in the United States. The armamentarium of treatment options for metastatic disease is limited and mostly ineffective with regards to eradicating cancer. However, there have been novel findings in the recent literature that substantiate the function of the microenvironment in breast cancer progression and the support of metastasis to tertiary sites such as bone marrow. The uncovered significance of the microenvironment in the pathophysiology of breast cancer metastasis has served to challenge previously widespread theories and introduce new perspectives for the future research to eradicate breast cancer. This paper delineates the current understanding of the molecular mechanisms involved in the interactions between breast cancer cells and the microenvironment in progression, metastasis, and dormancy. The information, in addition to other mechanisms described in bone marrow, is discussed in the paper.
    02/2012; 2012(11):721659. DOI:10.1155/2012/721659
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