92
J. C. Cawley
Figure 1. The cancer cell and its microenvironment. Integrins
Adhesion receptors a4b1 a5b1
aMb2 axb2
avb3 aEb7
Other adhesion receptors CD44
L-selectin (62L)
Table I. Expression and function of hairy cell adhesion receptors (from reference [1]). (CD)
Possible functions
(49d/29) Involved in binding to matrix (fibronectin, FN) and accessory cells via CD106 (VCAM) (49e/29) Involved together with a4b1 in binding to, and assembly of, FN matrix
(11b/18) Weakly expressed. Constitutes a monocytic feature of HCs and may be involved in endocytosis
(11c/18) Diagnostically important. Receptor for a number of ligands, including ICAM-1 (CD54), but function in HCs unclear
(51/61) Receptor for vitronectin (VN) and PECAM-1 (CD31). Important in HC motility
(103/b7) Diagnostically important. Receptor for E-cadherin; function unclear, but may be involved in localization in abdominal nodes
Highly expressed. HC receptor for hyaluronan. Several isoforms expressed. CD44H signals for FGF-2 (bFGF) production; V3 (heparin sulfate-containing isoform) acts as a co-receptor with FGFR-1 for stimulation of HC FN production by FGF-2 Little or no expression. Shed on cell activation
VCAM, vascular cell adhesion molecule; HC, hairy cell; ICAM-1, intercellular adhesion molecule-1; PECAM-1, platelet endothelial cell adhesion molecule-1; FGF-2, fibroblast growth factor 2; bFGF, basic fibroblast growth factor; FGFR-1, fibroblast growth factor receptor-1.
prominent infiltration in HCL of the spleen, where vitronectin is abundantly expressed in the red pulp [5]. Perhaps the best example of the effect of the
microenvironment on the cytokine production of HCs is the stimulation of fibroblast growth factor (FGF) production by HC interaction with hyalur- onan (HA) [4–6]. Here, interaction of HA with its receptor CD44 on HCs stimulates the production of autocrine FGF, which in turn causes the malignant cells to synthesize and secrete FN. This means that fibrosis is only found where HA is a prominent component of the extracellular matrix. HA is abun- dant in bone marrow and portal tracts, but absent from splenic red pulp and hepatic sinusoids. Conse- quently, fibrosis is not found at the latter two sites.
Effects of the intrinsic oncogenic transformation
Finally, it should be remembered that the above interactions are influenced by the malignant trans- formation of HCs. The nature of these oncogenic events is still unknown, but has been shown to involve constitutive activation of protein kinase Ce (PKCe), extracellular signal related kinase 1–2 (ERK1–2), and Rac [7–9] and the production of reactive oxygen
species (ROS) by the non-phagocytic NADPH (reduced nicotinamide adenine dinucleotide phos- phate) oxidase, NOX5 [9]. The constitutive activa- tion of the mitogen activated protein (MAP) kinase, ERK, contributes to the survival of HCs, while the active Rac is involved in both the distinctive surface morphology and motility of the malignant cells. The ROS contribute to the constitutive activation of HCs by inhibiting the phosphatase SHP-1.
Summary
The two-way interactions of HCs with their micro- environment are central to the biology of HCL and its pathogenesis. The mechanistic bases of most of these interactions are now defined. They involve the constitutive or stimulated production of cytokines by HCs and engagement of their intrinsically activated adhesive receptors by cellular or matrix ligands in the microenvironment. The bone marrow (BM) fibrosis of HCL is a particularly striking example of such interactions. Here, hyaluronan via its receptor CD44 stimulates HCs to produce FGF, which, in turn, causes the cells to synthesize and secrete FN, a major component of the fibrosis of the disease. Because HA is abundant in bone marrow, but not spleen, the fibrosis of HCL is conspicuous in BM, but not found
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