This study provides evidence that margin width of >1 cm is optimal and is an independent predictor of survival after hepatic resection for colorectal metastasis. However, subcentimeter resections are also associated with favorable outcome and should not preclude patients from undergoing resection.

Integrins and cadherins are considered to have distinct and opposing functions. Integrins are traditionally cited for their role in cell-substratum interactions, whereas cadherins are thought to mediate strong intercellular cohesion. Together, these adhesion systems play crucial roles in a wide variety of cellular and developmental processes including cell migration, morphology, differentiation and proliferation. In this manuscript we present evidence that integrins possess the ability to mediate strong intercellular cohesion when cells are grown as 3D aggregates. Much of the data elucidating the role of integrins as mediators of cell-extracellular matrix (ECM) interactions have been generated using conventional cell culture techniques in which cells are plated onto ECM-coated 2D surfaces. In vivo, cells are embedded in a 3D meshwork of ECM proteins. We hypothesized that, within this meshwork, integrin-ECM interactions may impart cohesivity to an aggregate of cells by linking adjacent cells together. To test this hypothesis, we transfected Chinese hamster ovary (CHO-B2) cells to express α5β1 integrin and found that these cells formed compact, spherical aggregates. We measured aggregate cohesivity using tissue surface tensiometry, a novel technique that quantifies cell-cell cohesivity of spheroids under physiological conditions. We determined that α5β1 integrin is capable of conferring strong cohesivity (σ=8.22±0.68 dynes/cm) to aggregates of α5-integrin-transfected cells. This cohesion was found to be independent of cadherin expression and was significantly greater than the cohesivity conferred onto CHO-B2 cells transfected with N-cadherin (σ=3.14±0.20 dynes/cm, P≤0.0001), a more traditional cell-cell cohesion system. Fibronectin-null CHO cells that express α5β1 integrin but do not secrete endogenous fibronectin do not form aggregates in fibronectin-depleted medium. Addition of increasing amounts of exogenous dimeric fibronectin to these cells resulted in a dose-dependent compaction. However, compaction failed to occur in the presence of fibronectin monomers. These data indicate that fibronectin is required for α5β1-mediated compaction and that the dimeric structure of fibronectin is essential for this process. Additionally, aggregate formation of the α5 integrin transfectants was inhibited by an RGD peptide thus confirming α5β1 integrin specificity. Collectively, these data confirm our hypothesis that α5β1 integrin acts through fibronectin to link adjacent cells together, thus promoting strong intercellular cohesion in 3D cellular aggregates.

Recent evidence demonstrates that interactions between different integrins that are present on the cell surface can strongly influence the adhesive function of individual receptors. In this report, we show that Chinese hamster ovary cells that express the integrin ␣ v ␤ 3 in the absence of ␣ 5 ␤ 1 demonstrate increased adhesion and migration on fibrinogen. Furthermore, ␣ v ␤ 3 -mediated adhesion to fibrinogen is not augmented by the soluble agonist, MnCl 2 , suggesting that ␣ v ␤ 3 exists in a higher affinity state in these cells. De novo expression of wild-type ␣ 5 ␤ 1 negatively regulates ␣ v ␤ 3 -mediated adhesion and migration. This effect is not seen with expression of a chimeric ␣ 5 ␤ 1 integrin in which the cytoplasmic portion of the ␣ 5 integrin subunit is replaced by the cytoplasmic portion of the ␣ 4 integrin. In addition, it does not require ligation of ␣ 5 ␤ 1 by fibronectin. Cells that express a constitutively active ␤ 3 integrin that contains a point mutation in the conserved membrane proximal region of the cytoplasmic tail, D723R, are resistant to the effect of ␣ 5 ␤ 1 expression. These data provide additional evidence of "cross-talk" between the integrins ␣ 5 ␤ 1 and ␣ v ␤ 3 , and support the idea that ␣ 5 ␤ 1 regulates ␣ v ␤ 3 -mediated ligand binding. This provides a relevant biological mechanism whereby variations in ␣ 5 ␤ 1 expression in vivo may modulate activation of ␣ v ␤ 3 to influence its adhesive function.Integrins are transmembrane glycoproteins that are the principle mediators of cell interactions with the extracellular matrix (ECM) 1 (1-3). They are composed of noncovalently associated ␣ and ␤ subunits, which together determine the ligand-binding specificity of the receptor. Integrin-ECM interactions are essential for a diverse variety of important biological processes, including embryogenesis, cell survival, and wound healing (4 -6). During wound healing, alterations in integrin expression coincide with deposition of a newly formed provisional ECM whose primary structural components include fibrinogen (FBG) and fibronectin (FN) (5, 7).Members of the ␤ 3 integrin family are the primary receptors that mediate cell interactions with FBG (8 -10). In platelets, the interaction of ␣ IIb ␤ 3 with FBG is dependent upon agoniststimulated signaling events that alter the ligand-binding function of the ␣ IIb ␤ 3 receptor, a process termed "integrin activation" (11). The adhesive function of ␣ v ␤ 3 also seems to be regulated by intracellular events as recent studies indicate that the basal affinity of this receptor varies both by intracellular location and among cell types (12-14). Activation of ␣ v ␤ 3 results in different functional states of the receptor that influence important integrin-dependent events, including cell migration, angiogenesis, and metastatic activity (14, 15). Although rapid regulation of ␣ v ␤ 3 function may represent a common mechanism for the modulation of cell-ECM interactions, little is known about the molecular events that affect receptor affinity.Recent evidence demo...

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