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Abstract

Prostate cancer frequently metastasizes to bone, and we propose that this process may be facilitated by the adhesion of metastatic cells to bone-derived type I collagen. We examined collagen receptor function and regulation in osteotropic PC-3 human prostatic carcinoma cells. PC-3 cell adhesion to immobilized human type I collagen was promoted by Mn2+ and Mg2+ ions and was RGD-independent. Antibodies directed against beta1 or alpha2 integrin subunits inhibited adhesion to collagen by 90% and 53%, respectively, suggesting involvement of the alpha2 beta1 receptor. Anti-alpha1 or anti-alpha3 antibodies had no effect on adhesion. Flow cytometry and immunoprecipitation of [35S]methionine-labeled cells demonstrated that alpha2 beta1 was the major collagen receptor expressed by PC-3 cells. The pretreatment of PC-3 cells with transforming growth factor-beta1 (TGF-beta1), a major bone-derived growth factor, caused a rapid (2 h) 2-fold increase in the de novo synthesis of alpha2 and beta1 integrin subunits, and also increased by 2- to 3-fold the adhesion and spreading of PC-3 cells on collagen. We conclude that alpha2 beta1 is the major collagen receptor employed by PC-3 cells, and that alpha2 beta1 upregulation by TGF-beta is associated with an increased adhesion and spreading on collagen. The data suggest that exposure of metastatic PC-3 cells to the high levels of TGF-beta in bone may promote their ability to adhere to bone-derived collagen, which may thereby facilitate the localization of metastatic cells in the skeleton.

p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion

“…Given that TGFbdependent effects upon cell adhesion required long exposure times (i.e., longer than 6 h), it is likely that changes in gene expression are necessary. This is supported by prior studies demonstrating that TGFb modulates expression of genes in various cell types associated with adhesion and motility, including: integrins, collagen, and PAI-1 (Ignotz and Massague, 1986;1987;Laiho and Keski-Oja, 1992;Kostenuik et al, 1997;Festuccia et al, 1999). It is also supported by the current study, where TGFb action upon cell adhesion required activation of Smads, which are known transcription factors.…”

“…We focused investigations upon human prostate because TGFb plays key regulatory roles in this cell type, and because dysregulation of TGFb signaling has been linked to human prostate cancer 1996a, b;Sehgal et al, 1996). We (Rohlff et al, 1998;Liu et al, 2002) and others (Hsing et al, 1996;Kostenuik et al, 1997;Wilding et al, 1989;Festuccia et al, 1999) have shown that TGFb is an important regulator of both cell growth, as well as adhesion and motility, in human prostate. Differential responsiveness to TGFb has been reported in metastatic versus primary prostate cells (Sehgal et al, 1996), while loss of TGFb receptor accompanies progression of human prostate cancer (Kim et al, 1996a).…”

“…Transforming growth factor b (TGFb) is a 25 kDa disulfide-linked homodimeric extracellular cytokine (Derynck and Feng, 1997), which in addition to modulating proliferation and differentiation, has been implicated in the regulation of cell adhesion and motility in a variety of cell types, including hepatocellular carcinoma cells (Bissell et al, 2001), glial cells (Xiao et al, 1996), melanoma cells (Mooradian et al, 1990), and breast cancer cells (Arteaga et al, 1990;Welch et al, 1990;Yin et al, 1999). In human prostate, TGFb has been shown to increase cell adhesion, motility, and invasion of PC3 cells (Kostenuik et al, 1997;Festuccia et al, 1999). Mechanistic studies have linked TGFb to a host of target genes related to the extracellular matrix, including fibronectin, collagen, integrins, and plasminogen activator inhibitor-1 (PAI-1) (Ignotz and Massague, 1986;Ignotz and Massague, 1987;Laiho and Keski-Oja, 1992;Kostenuik et al, 1997;Festuccia et al, 1999).…”

“…In human prostate, TGFb has been shown to increase cell adhesion, motility, and invasion of PC3 cells (Kostenuik et al, 1997;Festuccia et al, 1999). Mechanistic studies have linked TGFb to a host of target genes related to the extracellular matrix, including fibronectin, collagen, integrins, and plasminogen activator inhibitor-1 (PAI-1) (Ignotz and Massague, 1986;Ignotz and Massague, 1987;Laiho and Keski-Oja, 1992;Kostenuik et al, 1997;Festuccia et al, 1999).…”

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

“…To assess the specificity of TGF-β-mediated upregulation of integrin β3 as compared to other related integrin subunits, we evaluated how TGF-β alters expression of integrin αv, as well as a subfamily of β-integrin subunits that can also heterodimerize with integrin αv (integrin subunits β1, β5, β6 and β8). In addition, we evaluated integrin αIIb (glycoprotein-IIb), which is largely restricted to platelets and megakaryocyte-lineage cells but can also heterodimerize with integrin β3 (16), and integrin α2, which facilitates adhesion to type I collagen and is upregulated on prostate cancer lines in response to TGF-β (38). …”