Expression of Focal Adhesion Kinase in Acute Myeloid Leukemia Is Associated with Enhanced Blast Migration, Increased Cellularity, and Poor Prognosis

Récher, Christian; Ysebaert, Logic; Beyne‐Rauzy, Odile; Mas, Véronique Mansat‐De; Ruidavets, Jean‐Bernard; Cariven, Pascal; Demur, Cécile; Payrastre, Bernard; Laurent, Guy; Racaud‐Sultan, Claire

doi:10.1158/0008-5472.can-03-3005

Cited by 142 publications

(124 citation statements)

References 44 publications

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“…Finally, analyses of FAK expression levels in esophageal squamous cell carcinoma (Miyazaki et al, 2003), hepatocellular carcinoma (Itoh et al, 2004), acute myeloid leukemia (Recher et al, 2004) and ovarian cancer (Sood et al, 2004) tissue samples have found that FAK expression levels are inversely correlated with patient survival. As many cancer-related deaths are associated with elevated metastatic tumor burden, it is of interest to note that injection of malignant 4T1 cells expressing high levels of FAK led to the early death of 90% of injected animals within 21 days.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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Expression of focal adhesion kinase (FAK) is elevated in malignant breast cancer, yet the role of intrinsic FAK activity in promoting tumor progression remains undefined. Here, we have inhibited FAK activity or expression in murine 4T1 breast carcinoma cells via dominantnegative focal adhesion kinase-related non-kinase (FRNK) or anti-FAK short hairpin RNA (shRNA) expression, respectively. Neither FRNK nor FAK shRNA (B80% reduced FAK levels) affected 4T1 proliferation in culture, whereas reduced FAK activity or expression blocked 4T1 cell invasion through Matrigel and resulted in 2-3-fold lower urokinase plasminogen activator (uPA) expression. Control 4T1 cells implanted into mammary fat pads of BALB/c mice exhibited spontaneous metastasis to the lungs, to the peritoneal cavity, and resulted in 90% lethality within 21 days. Whereas FAK shRNAexpressing 4T1 cells formed tumors in mice with low levels of apoptosis, when mammary-injected, these cells did not exhibit lung metastasis after 21 days and caused only 40% lethality up to 60 days. Transient re-expression of wildtype but not kinase-dead FAK in 4T1 FAK shRNA cells promoted uPA production and mammary to lung metastasis within 7 days. In fact, stable human uPA overexpression in 4T1 FAK shRNA cells promoted Matrigel invasion and lung metastasis equal to 4T1 controls. Conversely, treatment with plasminogen activator inhibitor-1 or neutralizing antibody to uPA blocked Matrigel invasion of 4T1 control cells. These studies provide the first direct proof that FAK catalytic activity can facilitate metastatic breast cancer progression by regulating uPA expression.

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Section: Discussionmentioning

confidence: 99%

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Lim

et al. 2006

Oncogene

105

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“…Most likely, these and other factors interact with each other in a complex fashion to determine which blasts will circulate and which will stay in BM. [10][11][12][13] Irrespective of the cause, an increased tendency of blasts to circulate, when defined as the presence of higher blast percentages in PB than in BM, has prognostic value in ALL and MDS. The independent prognostic value of this phenomenon highlights the importance of exploring the causes behind it, and suggests that investigating its underlying causes may help in devising therapeutic strategies.…”

Section: P-valuementioning

confidence: 99%

Having a higher blast percentage in circulation than bone marrow: clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias

et al. 2005

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Determining the percentage of peripheral blood (PB) and bone marrow (BM) blasts is important for diagnosing and classifying acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Although most patients with acute leukemia or MDS have a higher percentage of BM blasts than PB blasts, the relative proportion is reversed in some patients. We explored the clinical relevance of this phenomenon in MDS (n ¼ 446), AML (n ¼ 1314), and acute lymphoblastic leukemia (ALL) (n ¼ 385). Among patients with MDS or ALL, but not AML, having a higher blast percentage in PB than in BM was associated with significantly shorter survival. In multivariate analyses, these associations were independent of other relevant predictors, including cytogenetic status. Our findings suggest that MDS and ALL patients who have a higher percentage of PB blasts than BM blasts have more aggressive disease. These data also suggest that MDS classification schemes should take into account the percentage of blasts in PB differently from the percentage of blasts in BM.

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“…A large number of reports describe an enhanced expression of FAK protein in a variety of human cancers, including sarcomas, astrocytomas and carcinomas of the breast, colon, thyroid, prostate, oral cavity, liver, stomach and ovary (see (McLean et al, 2005) and references herein). Furthermore, FAK overexpression has been correlated with the invasive potential of a tumour and poor patient prognosis Miyazaki et al, 2003;Recher et al, 2004;Sood et al, 2004). In a study of 106 matched pairs of larynx carcinomas and corresponding normal tissue, using immunohistochemistry, we have previously shown a significantly increased expression of FAK at the protein level in both the tumour tissues and the corresponding metastasis (Canel et al, 2006).…”

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confidence: 99%

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

et al. 2008

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Focal adhesion kinase (FAK) is considered intimately involved in cancer progression. Our previous research has demonstrated that overexpression of FAK is an early and frequent event in squamous cell carcinomas of the supraglottic larynx, and it is associated with the presence of metastases in cervical lymph nodes. The purpose of this study was to examine the functional role of FAK in the progression of head and neck squamous cell carcinomas (HNSCC). To this end, expression of FAK-related nonkinase (FRNK) or small interfering RNA (siRNA) against FAK was used to disrupt the FAK-induced signal transduction pathways in the HNSCC-derived SCC40 and SCC38 cell lines. Similar phenotypic effects were observed with the two methodological approaches in both cell lines. Decreased cell attachment, motility and invasion were induced by FRNK and FAK siRNA, whereas cell proliferation was not impaired. In addition, increased cell invasion was observed upon FAK overexpression in SCC cells. FRNK expression resulted in a downregulation of MMP-2 and MMP-9 expression. Interestingly, MMP-2 overexpression in FRNK-expressing cells rescued FRNK inhibition of cell invasion. This is the first demonstration of a direct rescue of impaired cell invasion by the re-expression of MMP-2 in a tumour cell type with decreased expression of functional FAK. Collectively, these data reported here support the conclusion that FAK enhances invasion of HNSCC by promoting both increased cell motility and MMP-2 production, thus providing new insights into possible therapeutic intervention strategies. Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer, comprising B50% of all malignancies in some developing nations. HNSCC is associated with severe disease-and treatment-related morbidity and has a 5-year survival rate of B50%. This survival rate has remained largely unchanged in the past three decades (Sankaranarayanan et al, 1998;Gonzalez-Botas and Vazquez Barro, 2006). A major determinant of the lethal progression of HNSCC is the spreading of the malignant cells to regional lymph nodes which represents a major prognostic indicator (Forastiere et al, 2001). Thus, attempts to identify the genes involved in metastasis are pivotal for the early prediction of HNSCC behaviour and development of novel molecular therapies. However, the identities of molecular alterations that endow cancer cells with these metastatic functions are largely unknown.The process of metastasis consists of sequential and selective steps including proliferation, motility, invasion, loss of cell -cell and cell -matrix adhesion, and remodelling of the extracellular matrix. A key factor involved in the control of cellextracellular matrix interactions is focal adhesion kinase (FAK), an intracellular tyrosine kinase protein that is localised to cellular focal contact sites (Schaller et al, 1992). Initially, phosphorylation of FAK occurs on its major autophosphorylation site, Tyr 397 . Phosphorylation of this tyrosine initiates a cascade of signal transdu...

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Expression of Focal Adhesion Kinase in Acute Myeloid Leukemia Is Associated with Enhanced Blast Migration, Increased Cellularity, and Poor Prognosis

Abstract: ABSTRACT

Cited by 142 publications

References 44 publications

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

Having a higher blast percentage in circulation than bone marrow: clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

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