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The Prostate 42:150–160 (2000)
Review Article
Dysregulated Expression of Growth Factors and
Their Receptors in the Development of
Prostate Cancer
Daniel Djakiew*
Department of Cell Biology, Division of Urology of the Department of Surgery, and the
Vincent T. Lombardi Cancer Center, Georgetown University Medical Center,
Washington, DC
KEY WORDS:
prostate cancer; growth factors; receptors; review
INTRODUCTION
Progression of prostate cancer is accompanied by
modifications in the expression of growth factors and
their receptors, many of which are the products of
protooncogenes or tumor suppressor genes. These alterations may take the form of up- or downregulation
of growth factors and/or their receptors as well as
changes from paracrine to autocrine mediation of
growth. A large body of literature implicating specific
growth factors and their receptors in the development
of prostate cancer has been derived from animal models and cell lines. However, man is unique in that no
other species develops prostate cancer, except under
extreme circumstances when induced with potent carcinogens. Hence, elucidation of growth factors and
their receptors implicated in the progression of prostate cancer in animal models and cell lines requires
verification with the etiology of human prostate cancer. Even then, the altered expression of some growth
factors and their receptors in prostate cancer may be
collateral rather than causal of the malignant transformation of human prostate epithelial cells. Although
many protooncogenes and tumor suppressor genes
that are not growth factors or growth factor receptors
play just as significant a role in the progression of
prostate cancer, the recent publication of an extensive
review on that topic [1] has ameliorated the necessity
for their inclusion herein. On the other hand, the recent rapid growth of research on growth factors and
their receptors in the prostate has provided a timely
opportunity to assess their contribution to the development of prostate cancer. Consequently, this review
focuses specifically on those growth factors and their
receptors, some of which function as protooncogenes
© 2000 Wiley-Liss, Inc.
and tumor suppressor genes, that appear to be risk
factors in the development of human prostate cancer.
EPIDERMAL GROWTH FACTOR FAMILY OF
PEPTIDES AND RECEPTORS
Malignant epithelial cells of the human prostate exhibit an enhanced capacity for autocrine expression of
epidermal growth factor (EGF) and the related family
member, transforming growth factor-␣ (TGF-␣) that
appears to circumvent a paracrine dependence on
stromal-cell derived EGF. Both EGF and heparinbinding EGF are secreted by smooth muscle stromal
cells [2,3]. EGF is also secreted by human epithelial
cancer cell lines [4,5]. Moreover, EGF and TGF-␣, both
signaling through the EGF receptor (EGFR), vary in
expression during malignant transformation [6]. Evidence that EGF signaling through the EGFR is important in prostate cancer cell proliferation is that 1) human prostate cancer cell lines produce EGF [4,5], 2)
human prostate cancer cells express EGFR in vitro [7]
and in vivo [8], 3) addition of EGF to cultures of prostate cancer cells stimulates growth [9], 4) addition of
anti-EGFR antibody inhibits the proliferation of prostate cancer cells in vitro [10] and in xenografted mice
in vivo [11], 5) EGFR blockade inhibits EGF- and insulin-like growth factor-I (IGF-I)-mediated transducGrant sponsor: Concern Foundation; Grant sponsor: NIH; Grant
number: R01 DK52626.
*Correspondence to: Daniel Djakiew, Ph.D., Department of Cell Biology, School of Medicine, Georgetown University, 3900 Reservoir
Rd., NW, Washington, DC 20007.
E-mail: djakiewd@gunet.georgetown.edu
Received 28 May 1999; Accepted 18 August 1999
Dysregulated Growth Factors and Receptors
tion of convergent mitogenic signaling pathways [12],
and 6) levels of EGFR may be higher in prostate cancer
than benign prostate [13], although several studies
have observed the opposite relationship [14,15]. Taken
together, it appears that the autocrine expression of
EGF and TGF␣ signaling through EGFR may contribute to the autonomous growth of human prostate cancer [6,16]. A second major function of EGF is the
stimulation of invasiveness of prostate cancer
[2,17,18]. This has been demonstrated in Boyden
chamber assays where 1) EGF promotes the chemomigration of human prostate cancer cells [2,17], 2) antagonism of EGFR function prevents EGF-stimulated
chemomigratory activity of human cancer cells [18],
and 3) clones of transfected cells expressing elevated
levels of EGFR invade across membranes to a greater
extent than parental cells [19]. Hence, these observations suggest that EGF/TGF␣ contributes to the autonomous growth of cancer cells and that EGF has a
pleiotropic effect on human prostate cancer cells, promoting both growth and invasiveness.
The EGFR family-related oncogenes HER-2/neu,
HER-3, and HER-4 are also differentially expressed in
the prostate [20]. The HER-2/neu gene product,
p185erbB-2, is not expressed in normal secretory epithelial cells [21], and may be expressed in basal cells [22]
but not luminal cells of benign prostatic hyperplasia
(BPH) tissues [21–23]. However, p185erbB-2 is expressed in the majority of epithelial cells in PIN and
human cancer cells [22,23]. Moreover, HER-2/neu
gene amplification and, to a lesser extent, p185erbB-2
protein expression correlate with increasing cancer
grade [24,25]. Experimental overexpression of
p185erbB-2 in normal epithelial cells produces a phenotype with an increased rate of proliferation and enhanced capacity for metastasis [26]. A similar pattern
of expression has been observed for the HER-3 gene
product, p160erbB-3, in BPH, prostatic intraepithelial
neoplasia (PIN), and cancer [22]. Interestingly, interleukin (IL)-6 induces tyrosine phosphorylation of both
p185erbB-2 and p160erbB-3, but not EGFR [27]. HER-4
receptor protein is strongly expressed in normal epithelial cells but not in prostate cancer [20]. The heregulin ligand (neu differentiation factor), which preferentially binds HER-3 and HER-4 gene products, is expressed in all stromal cells and basal cells, and in
approximately half of the luminal epithelial cells in
normal and BPH tissue, and is largely absent in cancer
[20]. Hence, heregulin may be a paracrine factor which
stimulates growth in vitro [20]. It then appears that
enhanced expression of p185erbB-2 and p160erbB-3 occurs with progression and that these oncogenes infer a
phenotype with an increased capacity for proliferation
and metastasis similar to that exhibited by EGFR and
its ligands EGF and TGF␣.
151
TRANSFORMING GROWTH FACTOR-BETA
FAMILY OF PEPTIDES AND RECEPTORS
The transforming growth factor (TGF) family consists of 1) TGF-␤ isoforms; and more distantly related
2) bone morphogenetic proteins; 3) the activins and
inhibins, all of which are differentially expressed in
the adult prostate; and 4) the developmentally expressed Mullerian inhibitory substance. In vitro, mammalian TGF-␤ isoforms 1–3 inhibit the proliferation of
normal human epithelial cells [28] and human cancer
cells [29], whereas, in vivo, TGF-␤1 enhances cancer
growth and metastasis [30]. This paradoxical role of
TGF-␤ in the regulation of cancer growth results from
modified expression of TGF-␤ receptors and the response of the host to TGF-␤. Normal prostate epithelial cells express TGF-␤1–3 to differing degrees [31],
whereas TGF-␤1–2 are overexpressed in human cancer [31]. As a consequence, both urinary TGF-␤1 and
plasma TGF-␤2 levels are elevated in cancer patients
[32]. TGF-␤ can recruit two distinct receptors, designated type I (RI) and type II (RII) receptors. This signaling pathway appears to be downregulated in prostate cancer. In this context, the TGF-␤ RI and RII proteins, which are abundantly expressed in normal
prostate epithelial cells, exhibit progressive reduction
of expression in primary cancer, and lymph node metastases [33]. Hence, even though cancer cells exhibit
an upregulation of TGF-␤1–2 expression [31], the
downregulation of TGF-␤ RI and RII expression [33]
appears to ameliorate the autocrine growth-inhibitory
effects of the TGF-␤s. This is further supported by the
observation that restoration of TGF-␤ RII expression in
a human prostate tumor cell line inhibits the growth of
xenograft tumors by induction of apoptosis [34].
Hence, human cancer cells that exhibit upregulation of
the TGF-␤s and downregulation of their receptors appear to exhibit host effects that facilitate cancer
growth. These cancer cells exhibit an immunosuppressive effect on lymphocyte action [35], and promote
angiogenesis, extracellular matrix deposition, and metastases [36].
The family of bone morphogenetic proteins (BMPs)
induces bone morphogenesis in vivo and has been
implicated in skeletal metastases of advanced prostate
cancer. BMP-2, -3, and -4 have been identified in normal epithelial cells and cancer in vitro [37]. However,
in vivo, BMP-6 expression is higher in organ-confined
cancer than in adjacent normal benign epithelial cells
[38]. BMP-6 expression is correlated with Gleason
score [38], pathologic stage [39,40], and bony metastases from prostate carcinoma [41]. The receptors
BMPR-IA, BMPR-IB, and BMPR-II are present on
prostatic epithelial cells [42,43]. BMPR-IB, but neither
BMPR-IA nor BMPR-II, is upregulated by androgens
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Djakiew
in the LNCaP cell line [42,43]. Moreover, BMPR-IA
stimulates growth, whereas BMPR-IB inhibits growth
in response to BMP-2 [43].
The activin ␤A and ␤B subunits are expressed in
normal human epithelial cells and cancer [44],
whereas the inhibin ␣ subunit appears to be absent in
both human and rodent prostate epithelial cells [45–
47]. Since the inhibin ␣ subunit may function as a
tumor suppressor, its absence may be involved with
the development of prostate cancer, since activin action cannot be opposed by inhibins [46,47]. However,
activins are expressed in human prostate cancer [44],
and inhibit prostate cancer growth [48,49] by induction of apoptosis [50]. Moreover, the activin-binding
protein, follistatin, inhibits activin action [50]. In the
normal prostate, follistatin is expressed by the stromal
cells and basal cells [50]. However, cancer acquires
expression of follistatin [45,48,50]. Hence, based on the
in vivo colocalization of follistatin and activins in human cancer, a resistance to the growth-inhibitory effects of activin was suggested to be conferred by follistatin [45]. This was confirmed in primary cultures of
human prostate carcinoma where treatment with activin was shown to inhibit epithelial cell proliferation;
conversely, treatment with follistatin enhanced epithelial cell proliferation [51].
FIBROBLAST GROWTH FACTOR FAMILY OF
PEPTIDES AND RECEPTORS
The fibroblast growth factor (FGF) family of peptides currently consists of at least 19 members, many
of which are expressed in the prostate to varying degrees. In the adult human prostate, FGF1 (acidic FGF)
is expressed at low levels or is undetectable [52]. Conversely, FGF-2 (basic FGF) is abundantly expressed
[52]. FGF-2 is produced by stromal cells [51] and acts
as a weak mitogen on the normal epithelium [53].
However, human cancer cells acquire autocrine expression of FGF-2 [56], which may further stimulate
cancer cell proliferation [57,58] and elevates the titer of
FGF-2 in the serum of prostate cancer patients [56,58].
In addition to the mitogenic action of autocrine FGF-2
on cancer cells, FGF-2 also enhances cell motility [59],
which may reflect an acquired capacity for metastasis.
The capacity of cancer cells to invade and metastasize
is a reflection of the ability of FGF-2 to regulate the
turnover of extracellular matrix by modulating the expression of proteases and promoting the synthesis of
collagen, fibronectin, and proteoglycans [60]. Autocrine FGF-2 expression by cancer also contributes to
the angiogenesis of primary [61] and metastatic cancers [62], thereby circumventing growth limitations of
diffusion in the supply of nutrients and removal of
waste products.
FGF-3, -4, -5, and -6 are oncogene products. FGF-3
(int-2 gene product) is probably not involved in localized prostate cancer [63]. This is supported by studies
of FGF-3 transgenic mice, which exhibit morphologically normal prostates [64]. Conversely, expression of
FGF-3 and FGF-5 has been reported to correlate with
progression to malignancy in the Dunning rat model
of prostate cancer [55]. Hence, the role of these oncogene products in human prostate cancer remains unclear.
FGF-7, also known as keratinocyte growth factor
(KGF), has been extensively investigated in rodent
models, with limited confirmatory studies in the human prostate. FGF-7 and its homologue FGF-10 are
androgen-regulated peptides [65,66], which are expressed predominantly in the stromal cells of the rat
[65,66] and human [67,68] prostate. Hence, FGF-7 and
FGF-10 were proposed as candidate andromedins
[65,66]. However, subsequent studies showed FGF-7
not to be androgen-regulated in vivo, thereby diminishing its status as a true andromedin [69]. FGF-7 has
also been localized to epithelial cells in the human
fetal prostate, normal adult prostate, and prostatic
cancer [70]. FGF-7 stimulates proliferation of prostate
epithelial cells [54] but not the LNCaP cancer cell line
[57]. In the rodent prostate, FGF-7 also stimulates proliferation of epithelial cells [65,71]. However, rodent
Dunning cancer cells exhibit a reduced response to
FGF-7 [55], attributed to exon switching in FGF receptor (FGFR) isoforms. In this context, epithelial cells of
the rat Dunning model appear to normally express the
FGFR2 (IIIb) isoform [55], which can bind FGF-7 and
FGF-10 as a mitogen [66,72]. However, cancer cells
express the alternatively spliced FGFR2 (IIIc) isoform
[55], which preferentially binds FGF-2 over FGF-7.
Both of these FGFR2 isoforms are present in human
prostate cancer [68], and even though androgeninsensitive human prostate cancer cell lines exhibit a
loss of FGFR2 (IIIb) in vitro [73], progression in exon
switching has not been observed in pathologic tissue
specimens [68], suggesting that the rodent model may
not be fully applicable. Nevertheless, the ability of autocrine FGF-2 to substitute for paracrine FGF-7 in cancer cells that exhibit the FGFR (IIIc) isoform may further facilitate proliferation of the cancer cells.
FGF-8, also known as androgen-induced growth
factor (AIGF), occurs in the epithelial cells of prostate
cancer as multiple isoforms [74]. It is expressed in LNCaP [75,76], DU-145, and PC-3 cancer cell lines [75,76],
and enhances the growth of the LNCaP cells [75].
FGF-8 is largely absent from the epithelial cells of normal prostate and BPH tissues, whereas it is overexpressed in cancer, and the level of expression appears
to be related to progression [77,78].
Dysregulated Growth Factors and Receptors
INSULIN-LIKE GROWTH FACTOR FAMILY OF
PEPTIDES, RECEPTORS, AND
BINDING PROTEINS
The insulin-like growth factor (IGF) system is characterized by complex interactions between the IGFs,
their receptors, high-affinity binding proteins, receptors for these binding proteins, and proteases. Epithelial cells cultured from normal prostate, BPH, and cancer have been reported not to secrete significant
amounts of IGF-I or IGF-II [79]. In contrast, IGF-II
mRNA and protein has been localized to human adenocarcinoma tissue of the prostate [80]. Several reports on human prostate cancer cell lines derived from
metastases (DU-145, PC3, LNCaP) indicate that these
cells do not secrete IGF-I [81] or IGF-II [83]. In contrast,
the same cell lines have been reported to secrete substantial amounts of IGF-I [82]. Prostatic stromal cells
secrete IGF-II [84], and possibly express IGF-I [85].
Irrespective of paracrine or autocrine origin, both
IGF-I and IGF-II stimulate the growth of epithelial
cells derived from primary cultures [79] and human
cancer cell lines [81]. Furthermore, IGFs appear to
stimulate the EGFR signal transduction cascade
[12,86]. Hence, elevated levels of serum IGF-I appear
to be a risk factor for the development of human prostate cancer [87–89].
The type 1 IGF receptor (IGF1R), which preferentially binds IGF-I, is expressed in epithelial cells cultured from normal prostate, BPH, and cancer [79] as
well as human prostate cancer cell lines derived from
metastases [81,86] and stromal cells [84]. Antagonism
of IGF1R function with IGF-I analogs inhibits the
growth of prostate cancer cell lines [82]. IGF1R mediates signal transduction upon binding either IGF-I or
IGF-II through its intrinsic tyrosine kinase activity
[90]. IGF2R does not contain intrinsic kinase activity
but does contain the mannose 6-phosphate recognition marker [90] which, upon binding IGF-II, directs
the IGF2R protein to lysosomes for degradation [91].
Hence, IGF2R may function as a negative growthregulatory molecule by depletion of ligand.
The ability of IGFs to mediate a growth response
via their receptors can be altered by interactions with
a variety of insulin-like growth factor-binding proteins (IGFBPs). Although receptors for some of the
IGFBPs have been described, their roles in the prostate
remain poorly understood. Epithelial cells cultured
from normal prostate, BPH, or cancer express IGFBP2, IGFBP-4 [79], and possibly IGFBP-3 [92], but not
IGFBP-1 [79]. Overexpression of inhibitory IGFBP-4
delays the onset of tumor formation in vivo [93]. Elevated levels of IGFBP-2 [94] and decreased levels of
IGFBP-3 [95] are present in the serum of patients with
prostate cancer. Increased levels of IGFBP-2 correlate
153
with increased prostate-specific antigen (PSA) in the
serum [94,95] and with cancer burden [96].
Proteolytic cleavage of IGFBPs reduces the affinity
for IGFs [97], facilitating greater interaction of IGF
with its receptor and increased mitogenic activity. Indeed, the serine protease, PSA, preferentially cleaves
IGFBP-3 [98] and IGFBP-5 [99], thereby stimulating
growth of prostatic epithelial cells [84] and reducing
the levels of IGFBP-3 in the serum [95]. The nerve
growth factor (NGF) gamma subunit, which shares
homology with PSA, also cleaves IGFBP-3, -4, and -6
[99]. However, NGF gamma is not expressed in the
human prostate. Hence, cleavage of IGFBP-3, -4, and
-6 by PSA [98–100] probably contributes to the bioavailability of IGF-I in the serum, consistent with the
elevated levels of IGF-I in the serum in prostate cancer
[87–89].
NERVE GROWTH FACTOR FAMILY OF
PEPTIDES AND RECEPTORS
Nerve growth factor (NGF) immunoreactive protein has been localized to normal epithelium [101,102]
and the stroma of normal, BPH, and cancer specimens
of human prostate [101,103,104]. Whether epithelial
NGF is synthesized de novo or endocytosed from the
stroma remains to be established. In any event, human
prostate stromal cells in vitro have been shown to secrete the long (35 kDa) and short (27 kDa) forms of
precursor NGF, and the partially processed cleavage
product (22 kDa form) of proNGF, whereas the mature (13 kDa) form of NGF␤ is not produced [105].
Stromal cell-derived precursor NGF stimulates the
proliferation of the TSU-pr1 human prostate cancer
cell line [103]. Furthermore, exogenous NGF␤ stimulates proliferation of the TSU-pr1 [106], DU-145, PC-3,
and LNCaP cell lines [107] in vitro, and promotes the
anchorage-independent growth of the androgenresponsive LNCaP [57] and androgen-refractory TSUpr1 [105] tumor cell lines. The androgen-refractory
cancer cell lines derived from metastases (DU-145, PC3, TSU-pr1) express NGF in an autocrine manner
[108], whereas the androgen-responsive LNCaP cell
line does not express the NGF gene [108]. Hence, it
appears that the normal prostate expresses stromal
cell-derived NGF for the paracrine regulation of epithelial cell growth, and that following human prostate
carcinogenesis, the androgen-refractory cancer cells
express autocrine NGF. In this manner, the prostate
cancer cells that produce autocrine NGF are able to
escape a paracrine dependence on stromal cellderived NGF. Since the pathology of malignant cell
migration within the human prostate is often by direct
extension around prostatic nerves, upregulation of autocrine neurotrophin expression in cancer may be as-
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Djakiew
sociated with invasion along the perineural space and
metastasis [108].
NGF is a ligand for the low-affinity p75 neurotrophin receptor (p75NTR), which is expressed to varying degrees in epithelial cells of the human prostate
[101,104]. Immunoblotting [109], immunofluorescent
[104], and immunohistochemical [110] studies have
shown that expression of the p75NTR protein declines
in human prostate cancer. Loss of expression of
p75NTR is correlated with cancer grade in organconfined disease [111]. Moreover, this protein is absent in four human cancer cell lines derived from metastases [109]. Loss of expression of p75NTR in prostate
cancer may be related to its role in the induction of
programmed cell death [106,112]. Reexpression of
p75NTR by stable and transient transfection showed
that p75NTR inhibits growth of prostate epithelium in
vitro, at least in part, by induction of programmed cell
death [106]. Hence, loss of p75NTR expression in prostate cancer cells appears to eliminate a potential programmed cell death pathway in these cells, thereby
facilitating the immortalization of these epithelia during carcinogenesis [111,112]. Consequently, p75NTR
has been suggested to be a candidate tumor suppressor gene in the human prostate [111,112].
Since expression of p75NTR is lost in human cancer,
NGF-mediated growth of cancer cells has been shown
to occur via the high-affinity Trk receptor [106,
108,110]. The Trk receptor is expressed in PIN, cancer
[110], and human cancer cell lines derived from metastases [106,108,110]. Members of the K252 family of
kinase inhibitors, the indolocarbazoles, selectively inhibit activity of the Trk receptors at nanomolar concentrations [113] and inhibit NGF-stimulated Trk
phosphorylation in the TSU-pr1 cancer cell line [114].
Concurrently, Trk-selective indolocarbazoles inhibit
growth of cancer cell lines in vitro [114] and in vivo
[115], further supporting a role of the Trk receptors in
NGF-mediated growth of human prostate cancer cells.
Although the Trk receptor was originally isolated as a
colon cancer oncogene [116], Trk mutations within the
human prostate have not been identified [117]. However, the absence of mutations in otherwise genetically
unstable prostate tumor DNA suggests that intact Trk
signaling pathways may be important in prostate cancer development [117].
VASCULAR ENDOTHELIAL GROWTH
FACTORS AND RECEPTORS
Vascular endothelial growth factor (VEGF) promotes angiogenesis in a wide variety of normal and
neoplastic tissues. In vivo, contradictory studies have
reported a complete lack of VEGF in BPH and epithelial cells [118], while another study observed two iso-
forms (VEGF165, VEGF189) of the protein in stromal
cells of BPH [119]. Conversely, a consensus of studies
observed VEGF expression in neuroendocrine cells
[120] and more abundantly in epithelial cells of the
normal prostate [121], in organ-confined cancer
[118,119], in human cancer cell lines derived from metastases, and in xenografts of prostate tumors [122].
Prostate tumor cell lines express the flk-1 receptor for
VEGF [123]. Exogenous VEGF appears to promote the
growth of xenograft tumors [124], and androgen ablation inhibits VEGF expression [122]. Moreover, treatment with anti-VEGF antibody inhibits the growth of
xenograft tumors [125] and their metastatic dissemination to the lungs [126]. Taken together, these observations suggest that human cancer cells express VEGF
for the angiogenesis of developing cancer masses,
thereby circumventing oxygen diffusion as a ratelimiting step in the growth of prostate cancers.
PLATELET-DERIVED GROWTH FACTORS
AND RECEPTORS
Platelet-derived growth factors (PDGF) exist as
dimers formed from A and B chains, which bind with
differing affinities to the PDGF␣ receptor and PDGF␤
receptor. PDGFs signal through their receptors to elicit
a diversity of cellular responses in vitro, including cell
proliferation, survival, transformation, and chemotaxis [127]. In vivo, contradictory studies have reported a
complete lack of either form of ligand or receptor in
BPH [128], while others have observed limited expression of the PDGF␤ receptor in BPH [129]. Conversely,
epithelial and stromal cells of prostatic intraepithelial
neoplasia (PIN) and human cancer express PDGF-A
and the PDGF␣ receptor [128,130], while PDGF-B and
the PDGF␤ receptor are either absent or weakly expressed [128,130]. Hence, PDGF-A ligand and its
PDGF␣ receptor may modulate autocrine growth in
BPH [129], PIN [130], and human cancer cells [128],
thereby playing a role in malignant transformation of
the prostate.
CYTOKINES AND RECEPTORS
Hepatocyte growth factor (HGF), also called scatter
factor, has been grouped with the cytokines based
upon the original definition of a cytokine as promoting cell (cyto) motility (kinetics). HGF is expressed in
the human prostate exclusively by the stroma
[131,132] and stimulates proliferation [57,133] and motility [133,134] of cancer cells. HGF binds to the c-met
protooncogene product, which is located exclusively
in epithelial cells of PIN [135], BPH [136], and human
cancer [133,135,136]. The proportion of tissue samples
that express c-met progressively increases from BPH
Dysregulated Growth Factors and Receptors
[136], to PIN [135], primary cancer [133,136], and metastases [133,136]. HGF induces motility and scattering
of cells from many organs, and the correlation of c-met
expression with malignant progression of cancer cells
suggests a role of c-met in metastases.
Although cytokines exert a variety of effects on cancer cells, there is little evidence to suggest that interleukin (IL)-1, IL-2, or interferon-␣, -␤, and -␥ are expressed during prostatic carcinogenesis. Conversely,
IL-6 is secreted in a paracrine manner from human
stromal cells [137] and in an autocrine manner from
human cancer cells [138,139]. Contradictory studies
have reported that IL-6 signals IL-6 receptors on cancer cells in vitro [139,140] and in tissue [140], either to
inhibit growth [137,141] via p27(Kip1)-mediated G1
arrest [142] or, conversely, to stimulate growth [143].
IL-6 and, to a greater extent, IL-10 also upregulate
expression of the tissue inhibitor of metalloproteinase-1 [144,145]; IL-10 also inhibits matrix metalloproteinase-2 and -9 secretion [146], consistent with an
overall inhibitory effect on cancer cells. Conversely,
IL-6 stimulation of growth may be a consequence of a
specific tumor cell phenotype that coexpresses
p185erbB-2 and/or p160/erbB-3, since IL-6 has been
shown to tyrosine phosphorylate p185erbB-2, which
forms a complex with the gp130 subunit of the IL-6
receptor, which can then mediate IL-6-dependent
growth [27]. This is consistent with reports of elevated
serum IL-6 correlating with tumor burden in patients
with clinically evident metastases [147,148]. Another
cytokine, tumor necrosis factor-alpha (TNF␣), inhibits
chemotaxis [141] and proliferation of human cancer
cell lines [141,149]. Moreover, TNF␣ is cytotoxic for
cancer cell lines [150] by inducing bcl-2-mediated [151]
programmed cell death [151,152]. The effect of TNF␣
is mediated by TNF-R1 (55 kDa) and TNF-R2 (75 kDa),
both of which are expressed by human prostate cancer
cell lines [153].
CONCLUSIONS
A distinct subset of growth factors, their receptors,
and associated binding proteins participate in the progression of human prostate cancer (Table I). Clearly,
the malignant progression of the prostate involves epithelial cell upregulation of autocrine growth factors
and their receptors, or autocrine acquisition of stromal
cell-derived growth factors by epithelial cells, both of
which facilitate the autonomous growth and metastasis of the tumor cells. The growth of tumor foci is
facilitated through the action of growth factors that
promote the proliferation of tumor cells, angiogenesis
growth factors that circumvent limitations of diffusion
on tumor volume, and the immunosuppressive TGF␤s
which circumvent the host’s defense mechanisms
(Table I). In addition, follistatin binding to activin con-
155
TABLE I. Dysregulated Expression of Growth Factors,
Their Receptors, Binding Proteins, and Related
Protooncogene and Tumor Suppressor Gene Products
in the Development of Prostate Cancer in Man
1. Acquisition/upregulation of autocrine growth factors
a. Proliferation (EGF, TGF␣, FGF-2, FGF-8, IGF-I, NGF,
PDGF-A)
b. Immunosuppression (TGF␤1, TGF␤2)
c. Angiogenesis (FGF-2, VEGF)
d. Metastasis (EGF, FGF-2, BMP-6?)
2. Dysregulation of growth factor-binding proteins
Follistatin, IGFBP-2, IGFBP-3
3. Upregulation of growth factor receptor protooncogene
products
EGFR, p185erB-2, p160erB-3, PDGF␣, c-met
4. Downregulation of tumor suppressor gene products
p75NTR, TGF␤ RI, TGF␤ RII, IGFRII?
fers resistance to the growth-inhibitory effects of activin. In some instances, the establishment of metastatic foci from primary tumors is regulated by the
same growth factors that promote proliferation of tumor cells (Table I). The upregulation of growth factor
receptor protooncogene products further facilitates
malignant progression of prostate tumor cells by enhancing the capacity of preexisting signal transduction
cascades (e.g., EGFR) or through the expression of a
transforming phenotype (e.g., p185erbB-2). Interestingly, the least prevalent transformation event appears to be the downregulation of growth factor receptor tumor suppressor gene products (e.g., TGF␤
RI). Clearly, not all of these characteristics of the malignant phenotype occur concurrently within all tumors. Nevertheless, the dysregulated expression of
several growth factors, their receptors, binding proteins, protooncogene products, and tumor suppressor
gene products (Table I) is associated with the development of the malignant phenotype. When this dysregulated expression occurs in the human prostate it
confers an enhanced growth advantage for the development of tumor foci. Moreover, since this dysregulated expression of specific growth factors, their receptors, binding proteins, protooncogene products, and
tumor suppressor gene products (Table I) is associated, to varying degrees, with mechanisms of neoplasia, they can be considered pathologic risk factors for
the development of prostate cancer.
ACKNOWLEDGMENTS
The author thanks Dr. David Bostwick, Dr. Tom
Crisp, and Dr. Bob Dickson for comments on this review. This work was supported, in part, by an EPA-
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ERG, Inc. contract. It does not necessarily reflect the
views and policies of the U.S. Environmental Protection Agency.
15.
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