вход по аккаунту



код для вставкиСкачать
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
prostate cancer; growth factors; receptors; review
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.
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.
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␣.
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
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].
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
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
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
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-
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 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 (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.
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].
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-
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,
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
EGFR, p185erB-2, p160erB-3, PDGF␣, c-met
4. Downregulation of tumor suppressor gene products
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.
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-
ERG, Inc. contract. It does not necessarily reflect the
views and policies of the U.S. Environmental Protection Agency.
1. Ho SM, Lee K-F, Lane K. Neoplastic transformation of the
prostate. In: Naz RK, editor. Prostate: basic and clinical aspects.
New York: CRC Press; 1998. p 73–114.
2. Rajan R, Vanderslice R, Kapur S, Lynch J, Thompson R, Djakiew D. Epidermal growth factor (EGF) promotes the chemomigration of a human prostate cancer cell line and EGF immunoreactive proteins are present at sites of metastasis in the
stroma of lymph nodes and medullary bone. Prostate 1996;28:
3. Freeman MR, Paul S, Kaefer M, Ishikawa M, Adam RM, Renshaw AA, Elenius K, Klagsbrun M. Heparin-binding EGF-like
growth factor in the human prostate: synthesis predominantly
by interstitial and vascular smooth muscle cells and action as a
carcinoma cell mitogen. J Cell Biochem 1998;68:323–328.
4. Connolly JM, Rose DP. Secretion of epidermal growth factor
and related polypeptides by the DU 145 human prostate cancer
cell line. Prostate 1989;15:177–186.
5. Connolly JM, Rose DP. Production of epidermal growth factor
and transforming growth factor-␣ by the androgen-responsive
LNCaP human prostate cancer cell line. Prostate 1990;16:209–
6. Scher HI, Sarkis A, Reuter V, Cohen D, Netto G, Petrylak D,
Lianes P, Fuks Z, Mendelsohn J, Cordon-Cardo C. Changing
pattern of expression of the epidermal growth factor receptor
and transforming growth factor-alpha in the progression of
prostatic neoplasms. Clin Cancer Res 1995;1:545–550.
7. Tillotson JK, Rose DP. Density-dependent regulation of epidermal growth factor receptor expression in DU-145 human prostate cancer cells. Prostate 1991;19:53–61.
8. Traish AM, Wotiz HH. Prostatic epidermal growth factor receptors and their regulation by androgens. Endocrinology
9. Jones HE, Eaton CL, Barrow D, Dutkowski CM, Gee JMW,
Griffiths K. Comparative studies of the mitogenic effects of
epidermal growth factor and transforming growth factor-alpha
and the expression of various growth factors in neoplastic and
non-neoplastic prostatic cell lines. Prostate 1997;30:219–231.
10. Fong C-J, Sherwood ER, Mendelson J, Lee C, Kozlowski JM.
Epidermal growth factor receptor monoclonal antibody inhibits constitutive receptor phosphorylation, reduces autonomous
growth, and sensitizes androgen-independent prostatic carcinoma cells to tumor necrosis factor-␣. Cancer Res 1992;52:
11. Prewett M, Rockwell P, Rockwell RF, Giorgio NA, Mendelsohn
J, Scher HI, Goldstein NI. The biological effects of C225, a
chimeric monoclonal antibody to the EGFR, on human prostate
carcinoma. J Immunother Emphasis Tumor Immunol 1996;19:
12. Putz T, Culig Z, Eder IE, Nessler-Menardi C, Bartsch G, Grunicke H, Uberall F, Klocker H. Epidermal growth factor (EGF)
receptor blockade inhibits the action of EGF, insulin-like
growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell
lines. Cancer Res 1999;59:227–233.
13. Davies P, Eaton CL. Binding of epidermal growth factor by
human normal, hypertrophic and carcinomatous prostate.
Prostate 1989;14:123–132.
14. Robertson CN, Robertson KM, Herzberg AJ, Kerns BJ, Dodge
RK, Paulson DF. Differential immunoreactivity of transforming growth factor alpha in benign, dysplastic and malignant
prostatic tissues. Surg Oncol 1994;3:237–242.
Turkeri LN, Sakr WA, Wykes SM, Grignon DJ, Pontes JE, Macoska JA. Comparative analysis of epidermal growth factor
receptor gene expression and protein product in benign, premalignant, and malignant prostate tissue: Prostate 1994;225:
Hofer DR, Sherwood ER, Bromberg WD, Mendelsohn J, Lee C,
Kozlowski JM. Autonomous growth of androgen-independent
human prostatic carcinoma cells: role of transforming growth
factor-␣. Cancer Res 1991;51:2780–2785.
Jarrard DF, Blitz BF, Smith RC, Patai BL, Rukstalis DB. Effect of
epidermal growth factor on prostate cancer cell line PC-3
growth and invasion. Prostate 1994;24:46–53.
Zolfaghari A, Djakiew D. Inhibition of chemomigration of the
TSU-pr1 human prostatic carcinoma cell line by inhibition of
EGF receptor function. Prostate 1996;28:232–238.
Xie H, Turner T, Wang M-H, Sing RK, Siegal GP, Wells A. In
vitro invasiveness of DU-145 human prostate carcinoma cells is
modulated by EGF receptor-mediated signals. Clin Exp Metastasis 1995;13:407–419.
Lyne JC, Melhem MF, Finley GG, Wen D, Liu N, Deng DH,
Salup R. Tissue expression of neu differentiation factor/
heregulin and its receptor complex in prostatic cancer and its
biologic effects on prostate cancer cells in vitro. Can J Sci Am
Zhou HE, Wan DS, Zhou J, Miller GJ, von Eschenbach AC.
Expression of cerb B-2/neu proto-oncogene in human prostatic
cancer tissues and cell lines. Mol Carcinog 1992;5:320–327.
Myers RB, Srivastava S, Oelschlager DK, Grizzle WE. Expression of p160erbB-3 and p185erbB-2 in prostatic intraepithelial
neoplasia and prostatic adenocarcinoma. J Natl Cancer Inst
Bostwick DG. c-erbB-2 oncogene expression in prostatic intraepithelial neoplasia: mounting evidence for a precursor role. J
Natl Cancer Inst 1994;86:1108–1110.
Ross JS, Sheenan C, Hayner-Buchan AM, Ambros RA, Kallakury BV, Kaufman R, Fisher HA, Muraca PJ. HER-2/neu
gene amplification status in prostate cancer by fluorescence in
situ hybridization. Hum Pathol 1997;28:827–833.
Ross JS, Sheenan C, Hayner-Buchan AM, Ambros RA,
Kallakury BV, Kaufman R, Fisher HA, Rifkin MD, Muraca PJ.
Prognostic significance of HER-2/neu gene amplification status by fluorescence in situ hybridization of prostate carcinoma.
Cancer 1997;79:2162–2170.
Marengo SR, Sikes RA, Anezinis P, Chang SM, Chung LW.
Metastasis induced by overexpression of p185neu-T after orthotopic injection into a prostatic epithelial cell line (NbE). Mol
Carcinog 1997;19:165–175.
Qui Y, Ravi L, Kung HJ. Requirements of ErbB2 for signaling
by interleukin-6 in prostate carcinoma cells. Nature 1998;393:
Story MT, Hopp KA, Molter M. Expression of transforming
growth factor beta 1 (TGF beta 1), -beta 2, and -beta 3 by
cultured human prostate cells. J Cell Physiol 1996;169:97–107.
Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Sensibar JA, Kim JH, Lee
C. Genetic change in transforming growth factor beta (TGFbeta) receptor type I gene correlates with insensitivity to TGFbeta I in human prostate cancer cells. Cancer Res 1996;56:44–48.
Barrack ER. TGF beta in prostate cancer: a growth inhibitor
that can enhance tumorigenicity. Prostate 1997;31:61–70.
Perry KT, Anthony CT, Steiner MS. Immunohistochemical localization of TGF beta 1, TGF beta 2, and TGF beta 3 in normal
and malignant human prostate. Prostate 1997;33:133–140.
Dysregulated Growth Factors and Receptors
32. Perry KT, Anthony CT, Case T, Steiner MS. Transforming
growth factor beta as a clinical biomarker for prostate cancer.
Urology 1997;49:151–155.
33. Guo Y, Jacobs SC, Kyprianou N. Down-regulation of protein
and mRNA expression for transforming growth factor-beta
(TGF-beta1) type I and type II receptors in human prostate
cancer. Int J Cancer 1997;16:573–579.
34. Guo Y, Kyprianou N. Restoration of transforming growth factor ␤ signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspace-1-mediated
apoptosis. Cancer Res 1999;59:1366–1371.
35. Wilding G. Response of prostate cancer cells to peptide growth
factors: transforming growth factor-␤. Cancer Surv 1991;11:
36. Steiner MS. Transforming growth factor-beta and prostate cancer. World Urol J 1995;13:329–336.
37. Harris SE, Harris MA, Mahy P, Wozney J, Feng JQ, Mundy GR.
Expression of bone morphogenetic protein messenger RNAs
by normal rat and human prostate and prostate cancer cell line.
Prostate 1994;24:204–211.
38. Barnes J, Anthony CT, Wall N, Steiner MS. Bone morphogenetic protein-6 expression in normal and malignant prostate.
World Urol J 1995;13:337–343.
39. Bentley H, Hamdy FC, Hart KA, Seid JM, Williams JL,
Johnstone D, Russell RG. Expression of bone morphogenetic
proteins in human prostatic adenocarcinoma and benign prostatic hyperplasia. Br J Cancer 1992;66:1159–1163.
40. Hamdy FC, Autzen P, Robinson MC, Horne CH, Neal DE,
Robson CN. Immunolocalization and messenger RNA expression of bone morphogenetic protein-6 in human benign and
malignant prostatic tissue. Cancer Res 1997;57:4427–4431.
41. Autzen P, Robson CN, Bjartell A, Malcolm AJ, Johnson MI,
Neal DE, Hamdy FC. Bone morphogenetic protein 6 in skeletal
metastases from prostate cancer and other common human
malignancies. Br J Cancer 1998;78:1219–1223.
42. Ide H, Katoh M, Sasaki H, Yoshida T, Aoki K, Nawa Y, Osada
Y, Sugimura T, Terada M. Cloning of human bone morphogenetic protein type IB receptor (BMPR-IB) and its expression in
prostate cancer in comparison with other BMPRs. Oncogene
43. Ide H, Yoshida T, Matsumoto N, Aoki K, Osada Y, Sugimura T,
Terada M. Growth regulation of human prostate cancer cells
by bone mophogenetic protein-2. Cancer Res 1997;57:5022–
44. Thomas TZ, Wang H, Nicalsen P, O’Bryan MK, Evans LW,
Groome NP, Pedersen J, Risbridger GP. Expression and localization of activin subunits and follistatins in tissues from men
with high grade prostate cancer. J Clin Endocrinol Metab 1997;
45. Thomas TZ, Chapman SM, Hong W, Gurusingfhe C, Mellor
SL, Fletcher R, Pedersen J, Risbridger GP. Inhibins, activins,
and follistatins: expression of mRNAs and cellular localization
in tissues from men with benign prostatic hyperplasia. Prostate
46. Furst BA, Zhang Z, Ying S-Y. Expression of activin and activin
receptors in a human prostatic carcinoma cell line DU145. Int J
Oncol 1995;7:239–243.
47. Ying S-Y, Zhang Z, Huang G. Expression and localization of
inhibin/activin subunits and activin receptors in the normal
rat prostate. Life Sci 1997;60:397–401.
48. Dalkin AC, Gilrain JT, Bradshaw D, Myers CE. Activin inhibition of prostate cancer cell growth: selective actions on androgen-responsive LNCaP cells. Endocrinology 1996;137:5230–
49. McPherson SJ, Thomas TZ, Wang H, Gurusinghe CJ, Ris-
bridger GP. Growth inhibitory response to activin A and B by
human prostate tumor cell lines, LNCaP and DU145. J Endocrinol 1997;154:535–545.
Wang GF, Tilly KI, Tilly JL, Preffer F, Schneyer AL, Crowley
WF, Sluss PM. Activin inhibits basal and androgen-stimulated
proliferation and induces apoptosis in the human prostatic
cancer cell line, LNCaP. Endocrinology 1996;137:5476–5483.
Wang Q, Tabatabaei S, Planz B, Lin CW, Sluss PM. Identification of an activin-follistatin growth modulatory system in the
human prostate: secretion and biological activity in primary
cultures of prostatic epithelial cells. J Urol 1999;161:1378–1384.
Mydlo JH, Michaeli J, Heston WD, Fair WR. Expression of
basic fibroblast growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma. Prostate 1988;13:241–247.
Story MT. Regulation of prostate growth by fibroblast growth
factors. World J Urol 1995;13:297–305.
Story MT, Hopp KA, Molter M, Meier DA. Characteristics of
FGF-receptors expressed by stromal cells and epithelial cells
cultured from normal and hyperplastic prostates. Growth Factors 1994;10:269–280.
Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan
WL. Exon switching and activation of stromal and embryonic
fibroblast growth factor (FGF)-FGF receptor genes in prostate
epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993;13:4513–4522.
Cronauer MV, Hittmair A, Eder IE, Hobisch A, Culig Z,
Ramoner R, Zhang J, Bartsch G, Reissigl A, Radmayr C, Thurnher M, Klocker H. Basic fibroblast growth factor levels in cancer cells and in the sera of patients suffering from proliferative
disorders of the prostate. Prostate 1997;31:223–233.
Chung LW, Li W, Gleave ME, Hsieh JT, Wu HC, Sikes RA,
Zhau HE, Bandyk MG, Logothetis CJ, Rubin JS, von Eschenbach AC. Human prostate cancer model: roles of growth factors and extracellular matrices. J Cell Biochem [Suppl] 1992;16:
Nakamoto T, Chang CS, Li AK, Chodak GW. Basic fibroblast
growth factor in human prostate cancer cells. Cancer Res 1992;
Pienta KJ, Isaacs WB, Vindivich D, Coffey DS. The effects of
basic fibroblast growth factor and suramin on cell motility and
growth of rat prostate cancer cells. J Urol 1991;145:199–202.
Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G. Structural characterization of biological functions of fibroblast
growth factor. Endocr Rev 1987;8:95–114.
Bigler SA, Deering RE, Brawer MK. A quantitative morphometric analysis of the microcirculation in prostate carcinoma.
Hum Pathol 1993;24:220–226.
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 1993;143:401–420.
Latil A, Baron JC, Cussenot O, Fournier G, Boccon-Gibod L, Le
Duc A, Lidereau R. Oncogene amplifications in early-stage human prostate carcinogenesis. Int J Cancer 1994;59:637–638.
Donjacour AA, Thomson AA, Cunha GR. Enlargement of the
ampullary gland and seminal vesicle, but not the prostate in
int-2/Fgf-3 transgenic mice. Differentiation 1998;62:227–237.
Yan G, Fukabori Y, Nikolaropolous S, Wang F, McKeehan WL.
Heparin-binding keratinocyte growth factor is a candidate
stromal-to-epithelial cell andromedin. Mol Endocrinol 1992;6:
Lu W, Luo Y, Kan M, McKeehan WL. Fibroblast growth factor10. A second candidate stromal to epithelial cell andromedin in
prostate. J Biol Chem 1999;274:12827–12834.
Ittman M, Mansukhani A. Expression of fibroblast growth fac-
tors (FGFs) and FGF receptors in human prostate. J Urol 1997;
Leung HY, Mehta P, Gray LB, Collins AT, Robson CN, Neal
DE. Keratinocyte growth factor expression in hormone insensitive prostate cancer. Oncogene 1997;28:1115–1120.
Thomson AA, Foster BA, Cunha GR. Analysis of growth factor
and receptor mRNAs during development of the rat seminal
vesicle and prostate. Development 1997;124:2431–2439.
McGarvey TW, Stearns ME. Keratinocyte growth factor and
receptor mRNA expression in benign and malignant human
prostate. Exp Mol Pathol 1995;63:52–62.
Cunha GR, Foster BA, Sugimura Y, Hom YK. Keratinocyte
growth factor as mediator of mesenchymal-epithelial interactions in the development of androgen target organs. Cell Dev
Biol 1996;7:1–8.
Igarashi M, Finch PW, Aaronson SA. Characterization of recombinant human FGF-10 reveals functional similarities with
KGF (FGF-7). J Biol Chem 1998;273:13230–13235.
Carstens RP, Eaton JV, Krigman HR, Walther PJ, Garcia-Blanco
MA. Alternative splicing of fibroblast growth factor receptor 2
(FGF-R2) in human prostate cancer. Oncogene 1997;18:3059–
Ghosh AK, Shankar DB, Shackleford GM, Wu K, T’Ang A,
Miller GJ, Zheng J, Roy-Burman P. Molecular cloning and characterization of human FGF8 alternative messenger RNA forms.
Cell Growth Differ 1996;7:1425–1434.
Tanaka A, Miyamoto K, Matsuo H, Yoshida H. Human androgen-induced growth factor in prostate and breast cancer cells:
its molecular cloning and growth properties. FEBS Lett 1995;
Schmitt JF, Hearn MT, Risbridger GP. Expression of fibroblast
growth factor-8 in adult rat tissues and human prostate carcinoma cells. J Steroid Biochem Mol Biol 1996;57:173–178.
Leung HY, Dickson C, Robson CN, Neal DE. Overexpression
of fibroblast growth factor-8 in human prostate cancer. Oncogene 1996;12:1833–1835.
Tanaka A, Furuya A, Yamasaki M, Hanai N, Kuriki K, Kamiakito T, Kobayashi Y, Yoshida H. High frequency of fibroblast
growth factor (FGF) 8 expression in clinical prostate cancer and
breast tissues, immunohistochemically demonstrated by a
newly established neutralizing monoclonal antibody against
FGF8. Cancer Res 1998;58:2053–2056.
Cohen P, Peehl DM, Lamson G, Rosenfeld RG. Insulin-like
growth factors (IGFs), IGF receptors, and IGF binding proteins
in primary cultures of prostatic epithelial cells. J Clin Endocrinol Metab 1991;73:401–407.
Tennant MK, Thrasher JB, Twomey PA, Drivdahl RH, Birnbaum RS, Plymate SR. Protein and messenger ribonucleic acid
(mRNA) for the type 1 insulin-like growth factor (IGF) receptor
is decreased and IGF-II mRNA is increased in human prostate
carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab 1996;81:3774–3782.
Iwamura M, Sluss PM, Casamento JB, Cockett ATK. Insulinlike growth factor-I: action and receptor characterization in
human prostate cancer cell lines. Prostate 1993;22:243–252.
Pietrzkowski Z, Mulholland G, Gomella L, Jameson BA, Wernicke L, Baserga R. Inhibition of growth of prostatic cancer cell
lines by peptide analogs of insulin-like growth factor I. Cancer
Res 1993;53:1102–1106.
Kimura G, Kasuya J, Giannini S, Honda Y, Mohan S, Kawachi
M, Akimoto M, Fujita-Yamaguchi Y. Insulin-like growth factor
(IGF) system components in human prostatic cancer cell lines:
LNCaP, DU-145, and PC-3 cells. Int J Urol 1996;3:39–46.
Cohen P, Peehl DM, Baker B, Lui F, Hintz RL, Rosenfeld RG.
Insulin-like growth factor axis abnormalities in prostatic stro-
mal cells from patients with benign prostatic hyperplasia. J
Clin Endocrinol Metab 1994;79:1410–1415.
Barni T, Vannelli BG, Sadri R, Pupilli C, Ghiandi P, Rizzo M,
Selli C, Serio M, Fiorelli G. Insulin-like growth factor-I (IGF-I)
and its binding protein IGFBP-4 in human prostatic hyperplastic tissue: gene expression and its cellular localization. J Clin
Endocrinol Metab 1994;78:778–783.
Connolly JM, Rose DP. Regulation of DU-145 human prostate
cancer cell proliferation by insulin-like growth factors and its
interaction with the epidermal growth factor autocrine loop.
Prostate 1994;24:167–175.
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollack M. Plasma insulin-like growth
factor-I and prostate cancer risk: a prospective study. Science
Cohen P. Serum insulin-like growth factor-I levels and prostate
cancer risk-interpreting the evidence. J Natl Cancer Inst 1998;
Wolk A, Mantzoros CS, Andersson S-O, Bergstrom R, Signorello LB, Lagiou P, Adami H-O, Trichopoulos D. Insulin-like
growth factor-I levels and prostate cancer risk: a populationbased, case-control study. J Natl Cancer Inst 1998;90:876–879.
Kornfeld S. Structure and function of mannose 6-phosphate/
insulin-like growth factor II receptor. Annu Rev Biochem 1992;
Oka Y, Rozek LM, Czech MP. Direct demonstration of rapid
insulin-like growth factor II receptor internalization and recycling in rat adipocytes. Insulin stimulates 125I-insulin-like
growth factor degradation by modulating the IGF-II receptor
recycling process. J Biol Chem 1985;260:9435–9442.
Birnbaum RS, Ware JL, Plymate SR. Insulin-like growth factorbinding protein-3 expression and secretion by cultures of human prostate epithelial cells and stromal fibroblasts. J Endocrinol 1994;141:535–540.
Damon SE, Maddison L, Ware JL, Plymate SR. Overexpression
of an inhibitory insulin-like growth factor binding protein
(IGFBP), IGFBP-4, delays onset of prostate tumor formation.
Endocrinology 1998;139:3456–3464.
Cohen P, Peehl D, Stamey TA, Wilson KF, Clemmons DR,
Rosenfeld RG. Elevated levels of insulin-like growth factorbinding protein-2 in the serum of prostate cancer patients. J
Clin Endocrinol Metab 1993;76:1031–1035.
Kanteny H, Madjar Y, Dagan Y, Levi J, Papa MZ, Pariente C,
Goldwasser B, Karasik A. Serum insulin like growth factor
binding protein-2 (IGFBP-2) is increased and IGFBP-3 is decreased in human prostate cancer cell lines. J Clin Endocrinol
Metab 1993;77:229–233.
Ho PJ, Baxter RC. Insulin-like growth factor-binding protein-2
in patients with prostate carcinoma and benign hyperplasia.
Clin Endocrinol 1997;46:145–154.
Cohick WS, Clemmons DR. The insulin-like growth factors.
Annu Rev Physiol 1993;55:131–153.
Cohen P, Graves HCB, Peehl DM, Kamarei M, Guidice LC,
Rosenfeld RG. Prostate-specific antigen (PSA) is an insulin-like
growth factor binding protein-3 protease found in seminal
plasma. J Clin Endocrinol Metab 1992;75:1046–1053.
Rajah R, Bhala A, Nunn SE, Peehl DM, Cohen P. 7S nerve
growth factor is an insulin-like growth factor-binding protein
protease. Endocrinology 1996;137:2676–2682.
Cohen P, Peehl DM, Graves HCB, Rosenfeld RG. Biological
effects of prostate specific antigen as an insulin-like growth
factor binding protein-3 protease. J Endocrinol 1994;142:407–
MacGrogan D, Saint-Andre J-P, Dicou E. Expression of nerve
growth factor and nerve growth factor receptor genes in hu-
Dysregulated Growth Factors and Receptors
man tissues and in prostatic adenocarcinoma cell lines. J Neurochem 1992;59:1381–1391.
Paul AB, Grant ES, Habib FK. The expression and localization
of ␤-nerve growth factor (␤-NGF) in benign and malignant
human prostate tissue: relationship to neuroendocrine differentiation. Br J Cancer 1992;74:1990–1996.
Djakiew D, Delsite R, Pflug B, Wrathall J, Lynch JH, Onoda M.
Regulation of growth by a nerve growth factor-like protein
which modulates paracrine interactions between a neoplastic
epithelial cell line and stromal cells of the human prostate.
Cancer Res 1991;51:3304–3310.
Graham C, Lynch JH, Djakiew D. Distribution of nerve growth
factor-like protein and nerve growth factor receptor in human
benign prostatic hyperplasia and prostatic adenocarcinoma. J
Urol 1992;147:1444–1447.
Delsite R, Djakiew D. Characterization of nerve growth factor
precursor protein expression by human prostate stromal cells:
a role in selective neurotrophin stimulation of prostate epithelial cell growth. Prostate 1999;41:39–48.
Pflug B, Djakiew D Expression of p75NTR in a human prostate
epithelial tumor cell line reduces NGF induced cell growth by
activation of programmed cell death. Mol Carcinog 1998;23:
Angelsen A, Sandvik AK, Syversen U, Stridsberg M, Waldum
HL. NGF-␤, NE-cells and prostatic cancer cell lines. Scand J
Urol Nephrol 1998;32:7–13.
Dalal R, Djakiew D. Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial cells and stromal cells of the
human prostate. Mol Cell Endocrinol 1997;134:15–22.
Pflug BR, Onoda M, Lynch JH, Djakiew D. Reduced expression
of the low affinity nerve growth factor receptor in benign and
malignant human prostate tissue and loss of expression in four
human metastatic prostate tumor cell lines. Cancer Res 1992;
Pflug BR, Dionne CA, Kaplan DR, Lynch JH, Djakiew D. Expression of the Trk high affinity nerve growth factor receptor
in the human prostate. Endocrinology 1995;136:262–268.
Perez M, Regan T, Pflug B, Lynch J, Djakiew D. Loss of the low
affinity nerve growth factor receptor during malignant transformation of the human prostate. Prostate 1997;30:274–279.
Djakiew D, Delsite R, Dalal R, Pflug B. The role of the low
affinity nerve growth factor receptor and the high affinity Trk
receptor in human prostate carcinogenesis. Radiat Oncol Invest 1996;3:333–339.
Berg MM, Sternberg DW, Parada LF, Chao MV. K252a inhibits
nerve growth factor-induced trk proto-oncogene tyrosine
phosphorylation and kinase activity. J Biol Chem 1992;267:13–
Delsite R, Djakiew D. Anti-proliferation effect of the kinase
inhibitor K252a on human prostatic carcinoma cell lines. J Androl 1996;17:481–490.
Dionne C, Jani J, Camoratto AM, Emerson E, Neff NT, Vaught
J, Murakata C, Djakiew D, Lamb J, Bova S, George D, Isaacs J.
Cell-cycle independent death of prostate adenocarcinoma is
induced by the Trk tyrosine kinase inhibitor CEP-751. Clin
Cancer Res 1998;4:1887–1898.
Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene
formed by the fusion of truncated tropomyosin and protein
tyrosine kinase sequences. Nature 1986;319:743–748.
George DJ, Suzuki H, Bova GS, Isaacs JT. Mutational analysis
of the TrkA gene in prostate cancer. Prostate 1998;36:172–180.
Ferrer FA, Miller LJ, Andrawis RI, Kurtzman SH, Albertsen
PC, Laudone VP, Kreutzer DL. Vascular endothelial growth
factor (VEGF) expression in human prostate cancer: in situ and
in vitro expression of VEGF by human prostate cancer cells. J
Urol 1997;157:2329–2333.
Jackson MW, Bentel JM, Tilley WD. Vascular endothelial
growth factor (VEGF) expression in prostate cancer and benign
prostatic hyperplasia. J Urol 1997;157:2323–2338.
Guy L, Begin LR, Al-Othman K, Chevalier S, Aprikian AG.
Neuroendocrine cells of the verumontanum: a comparative immunohistochemical study. Br J Urol 1998;82:738–743.
Campbell CL, Savarese DM, Quesenberry PJ, Savarese TM.
Expression of multiple angiogenic cytokines in cultured normal human prostate epithelial cells: predominance of vascular
endothelial growth factor. Int J Cancer 1999;15:868–874.
Joseph IB, Isaacs JT. Potentiation of the antiangiogenic ability
of linomide by androgen ablation involves down-regulation of
vascular endothelial growth factor in human androgenresponsive prostatic cancers. Cancer Res 1997;57:1054–1057.
Balbay MD, Pettaway CA, Kuniyasu H, Inoue K, Ramirez E, Li
E, Fidler IJ, Dinney CP. Highly metastatic human prostate cancer growing within the prostate of athymic mice overexpresses
vascular endothelial growth factor. Clin Cancer Res 1999;5:
Gridley DS, Andres ML, Slater JM. Enhancement of prostate
cancer xenograft growth with whole-body radiation and vascular endothelial growth factor. Anticancer Res 1997;17:923–
Borgstrom P, Bourdon MA, Hillan KJ, Sriramarao P, Ferrara N.
Neutralizing anti-vascular endothelial growth factor antibody
completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo. Prostate 1998;35:1–10.
Melnyk O, Zimmerman M, Kim KJ, Shuman M. Neutralizing
anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a
pre-clinical model. J Urol 1999;161:960–963.
Kim HE, Han SJ, Kasaza T, Han R, Choi HS, Palmer KC, Kim
HR. Platelet-derived growth factor (PDGF)-signaling mediates
radiation-induced apoptosis in human prostate cancer cells
with loss of p53 function. Int J Radiat Oncol Biol Phys 1997;39:
Fudge K, Wang CY, Stearns ME. Immunohistochemical analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor alpha and beta receptor expression in
benign prostatic hyperplasias and Gleason-graded human
prostatic adenocarcinomas. Mod Pathol 1994;7:549–554.
Vlahos CJ, Kriauciunas TD, Gleason PE, Jones JA, Eble JN,
Salvas D, Falcone JF, Hirsch KS. Platelet-derived growth factor
induces proliferation of hyperplastic human prostatic stromal
cells. J Cell Biochem 1993;52:404–413.
Fudge K, Bostwick DG, Stearns ME. Platelet-derived growth
factor A and B chains and the alpha and beta receptors in
prostatic intraepithelial neoplasia. Prostate 1996;29:282–286.
Seslar SP, Nakamura T, Byers SW. Regulation of fibroblast
hepatocyte growth factor/scatter factor expression by human
breast carcinoma cell lines and peptide growth factors. Cancer
Res 1993;53:1233–1238.
Kurimoto S, Moriyama N, Horie S, Sakai M, Kameyama S,
Akimoto Y, Hirano H, Kawabe K. Co-expression of hepatocyte
growth factor and its receptor in human prostate cancer. Histochem J 1998;30:27–32.
Humphrey PA, Zhu X, Zarneger R, Swanson PE, Ratliff TL,
Volmer RT, Day ML. Hepatocyte growth factor and its receptor
(c-MET) in prostatic carcinoma. Am J Pathol 1995;147:386–396.
Nishimura K, Kitamura M, Takada S, Nonomura N, Tsujimura
A, Matsumiya K, Miki T, Matsumoto K, Okuyama A. Regulation of invasive potential of human prostate cancer cell lines by
hepatocyte growth factor. Int J Urol 1998;5:276–281.
135. Myers RB, Grizzle WE. Biomarker expression in prostatic intraepithelial neoplasia. Eur Urol 1996;30:153–166.
136. Pisters LL, Troncoso P, Zhau HE, Li W, von Eschenbach AC,
Chung LW. c-met proto-oncogene expression in benign and
malignant human prostate tissues. J Urol 1995;154:293–298.
137. Degeorges A, Tatoud R, Fauvel-Lafeve F, Podgorniak MP, Millot G, de Cremoux P, Calvo F. Stromal cells from human benign prostate hyperplasia produce a growth-inhibitory factor
for LNCaP prostate cancer cells, identified as interleukin-6. Int
J Cancer 1996;68:207–214.
138. Borsellino N, Belldegrun A, Bonavida B. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum
and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res 1995;55:4633–4639.
139. Siegall CB, Scwab G, Nordan RP, Fitzgerald DJ, Pastan I. Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. Cancer Res 1990;50:7786–7788.
140. Siegsmund MJ, Yamazaki H, Pastan I. Interleukin 6 receptor
mRNA in prostate carcinomas and benign prostate hyperplasia. J Urol 1994;151:1396–1399.
141. Ritchie CK, Andrews LR, Thomas KG, Tindall DJ, Fitzpatrick
LA. The effects of growth factors associated with osteoblasts on
prostate carcinoma proliferation and chemotaxis: implications
for the development of metastatic disease. Endocrinology 1997;
142. Mori S, Murakami-Mori K, Bonavida B. Interleukin-6 induces
G1 arrest through induction of p27(Kip1), a cyclin-dependent
kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun 1999;257:609–
143. Borsellino N, Bonavida B, Ciliberto G, Toniatti C, Travalis S,
D’Alessandro N. Blocking signaling through the gp130 receptor chain by interleukin-6 and oncostatin M inhibit PC-3 cell
growth and sensitizes the tumor cells to etoposide and cisplatin-mediated cytotoxicity. Cancer 1999;85:134–144.
144. Stearns M, Wang M, Stearns ME. Cytokine (IL-10, IL-6) induction of tissue inhibitor of metalloproteinase 1 in primary human prostate tumor cell lines. Oncology Res 1995;7:173–181.
145. Wang M, Fudge K, Rhim JS, Stearns ME. Cytokine regulation
of the matrix metalloproteinases and their inhibitors in human
papillomavirus-18 transformed human prostatic tumor cell
lines. Oncol Res 1996;8:303–315.
146. Stearns ME, Rhim JS, Wang M. Interleukin 10 (IL-10) inhibition
of primary human prostate cell-induced angiogenesis: IL-10
stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)/MMP-9 secretion.
Clin Cancer Res 1999;5:189–196.
147. Akimoto S, Okumura A, Fuse H. Relationship between serum
levels of interleukin-6, tumor necrosis factor-alpha and bone
turnover markers in prostate cancer patients. Endocr J 1998;45:
148. Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT,
Thompson TC. Elevated levels of circulating interleukin-6 and
transforming growth factor-beta1 in patients with metastatic
prostatic carcinoma. J Urol 1999;161:182–187.
149. Nakajima Y, DelliPizzi A, Mallouh C, Ferreri NR. Effect of
tumor necrosis factor-alpha and interferon-gamma on the
growth of human prostate cancer cell lines. Urol Res 1995;23:
150. Sherwood ER, Pitt Ford TR, Lee C, Kozlowski JM. Therapeutic
efficacy of recombinant tumor necrosis factor alpha in an experimental model of human prostatic carcinoma. J Biol Response Mod 1990;9:44–52.
151. Herrmann JL, Beham AW, Sarkiss M, Chiao PJ, Rands MT,
Bruckheimer EM, Brisbay S, McDonnell TJ. Bcl-2 suppresses
apoptosis resulting from disruption of the NF-kappa B survival pathway. Exp Cell Res 1997;237:101–109.
152. Sensibar JA, Sutkowski DM, Raffo A, Buttyan R, Griswold MD,
Sylvester MD, Kozlowski JM, Lee C. Prevention of cell death
induced by tumor necrosis factor alpha in LNCaP cells by
overexpression of sulfated glycoprotein-2 (clusterin). Cancer
Res 1995;55:2431–2437.
153. Nakajima Y, DelliPizzi A, Mallouh C, Ferreri NR. TNF-mediated cytotoxicity and resistance in human prostate cancer cell
lines. Prostate 1996;29:296–302.
Без категории
Размер файла
137 Кб
Пожаловаться на содержимое документа