Mechanisms underlying stimulation of
platelet-derived growth factor (PDGF) beta-receptors expressed on connective tissue cells in human colorectal
adenocarcinoma were investigated in this study.
PDGF-AB/BB, but not
PDGF receptors, was expressed by
tumor cells in situ, as well as in
tumor cell isolates of low passage from human colorectal
adenocarcinoma. In an experimental co-culture system,
conditioned medium from
tumor cells only marginally activated PDGF beta-receptors expressed on fibroblasts. In contrast, co-culturing of the two cell types led to a marked
PDGF beta-receptor activation. Functional
PDGF-AB/BB was found to be associated with
heparinase-I-sensitive components on the
tumor cell surface.
PDGF-AB/BB, isolated from
heparinase-I-sensitive cell surface components, induced a marked activation of PDGF beta-receptors. Furthermore, co-culturing
tumor cells together with fibroblasts led to a sustained activation of PDGF beta-receptors expressed on fibroblasts. Double immunofluorescence staining of tissue sections from human colorectal
adenocarcinoma, combined with computer-aided image analysis, revealed that nonproliferating
tumor cells were the predominant cellular source of
PDGF-AB/BB in the
tumor stroma. In addition,
PDGF-AB/BB-expressing
tumor cells were found juxtapositioned to microvascular cells expressing activated PDGF beta-receptors. Confocal microscopy revealed a cytoplasmic and cell-membrane-associated expression of
PDGF-AB/BB in
tumor cells situated in the stroma. In contrast, epithelial cells situated in normal or tumorous acinar structures revealed only a cell-membrane-associated
PDGF-AB/BB expression. The is vitro and in situ results demonstrate that
tumor cells not only facilitate but also have the ability to modulate connective tissue cell responsiveness to
PDGF-AB/BB in a paracrine fashion, through direct cell-cell interactions in human colorectal
adenocarcinoma.