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n3:pmcid
PMC0
bibo:doi
10.1371%2Fjournal.pone.0004992
n7:contains
_:vb5045913 _:vb5045940 _:vb5045930
Subject Item
_:vb5045913
rdf:type
n7:Section
dc:title
introduction
n7:contains
_:vb5045914 _:vb5045915 _:vb5045916 _:vb5045917 _:vb5045918 _:vb5045919 _:vb5045920 _:vb5045921 _:vb5045922 _:vb5045923 _:vb5045924 _:vb5045925 _:vb5045926 _:vb5045927 _:vb5045928 _:vb5045929
Subject Item
_:vb5045914
rdf:type
n3:Context
rdf:value
Tumors are thought to develop stroma from several sources, thus the characterization by Wels et al. of tumor-associated stromal cells as “migratory neighbors and distant invaders” [>>1<<]. Data in the literature currently support four origins: (1) the recruitment of resident tissue stem cells, (2) epithelial to mesenchymal transition of the tumor parenchyma, (3) fibroblast recruitment into the tumor stroma, and (4)
n3:mentions
n2:18316475
Subject Item
_:vb5045915
rdf:type
n3:Context
rdf:value
the recruitment of resident tissue stem cells, (2) epithelial to mesenchymal transition of the tumor parenchyma, (3) fibroblast recruitment into the tumor stroma, and (4) recruitment of bone marrow-derived cells from the circulation [>>2<<]–[5].
n3:mentions
n2:16394272
Subject Item
_:vb5045916
rdf:type
n3:Context
rdf:value
recruitment of resident tissue stem cells, (2) epithelial to mesenchymal transition of the tumor parenchyma, (3) fibroblast recruitment into the tumor stroma, and (4) recruitment of bone marrow-derived cells from the circulation [2]–[>>5<<].
n3:mentions
n2:15833851
Subject Item
_:vb5045917
rdf:type
n3:Context
rdf:value
within the tumor microenvironment into fibroblastic-like cells that have been variably referred to as; myofibroblasts, tumor-associated (myo)fibroblasts (TAF), carcinoma-associated fibroblasts (CAF), fibrocytes or pericytes [>>6<<]. TAF have been shown to play an important role in tumor formation, growth and metastasis.
n3:mentions
n2:16840726
Subject Item
_:vb5045918
rdf:type
n3:Context
rdf:value
The presence of fibroblast populations within human tumors is associated with poor outcome and an increase in metastatic potential [>>7<<], [8]. These TAF are associated with expression of factors involved in degradation of matrix proteins, angiogenesis and promotion of cell growth: matrix metalloproteinases (MMP), plasminogen activator inhibitor-1, vascular endothelial
n3:mentions
n2:17404090
Subject Item
_:vb5045919
rdf:type
n3:Context
rdf:value
The presence of fibroblast populations within human tumors is associated with poor outcome and an increase in metastatic potential [7], [>>8<<]. These TAF are associated with expression of factors involved in degradation of matrix proteins, angiogenesis and promotion of cell growth: matrix metalloproteinases (MMP), plasminogen activator inhibitor-1, vascular endothelial growth
n3:mentions
n2:15627894
Subject Item
_:vb5045920
rdf:type
n3:Context
rdf:value
matrix proteins, angiogenesis and promotion of cell growth: matrix metalloproteinases (MMP), plasminogen activator inhibitor-1, vascular endothelial growth factor (VEGF), insulin growth factor (IGF-2) and hepatocyte growth factor (HGF) [>>9<<]. The TAF population differs from a normal fibroblastic phenotype because of its rich source of tumor-growth-promoting factors, pro-angiogenic factors and expression of myofibroblastic characteristics.
n3:mentions
n2:14639599
Subject Item
_:vb5045921
rdf:type
n3:Context
rdf:value
including stromelysin-1 (SL-1), thrombospondin-1 (Tsp-1) and tenascin-C (Tn-C); (3) myofibroblast/provascularizing potential including desmin, alpha-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) [>>10<<]; and lastly, (4) growth factors, transforming growth factor-beta (TGF-β), HGF/scatter factor (SF), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF).
n3:mentions
n2:11962761
Subject Item
_:vb5045922
rdf:type
n3:Context
rdf:value
Our group originally demonstrated the capacity of MSC, also known as multipotent stromal cells, to home to tumors and participate in tumor stroma formation, suggesting MSC as a potential source of stroma [>>11<<], [12]. MSC are a heterogeneous population of connective tissues progenitors found in many locations, such as adipose tissue, dermis, and bone marrow. The tropism of MSC for tumors is thought to be due to similarity in factors secreted by
n3:mentions
n2:12097260
Subject Item
_:vb5045923
rdf:type
n3:Context
rdf:value
Our group originally demonstrated the capacity of MSC, also known as multipotent stromal cells, to home to tumors and participate in tumor stroma formation, suggesting MSC as a potential source of stroma [11], [>>12<<]. MSC are a heterogeneous population of connective tissues progenitors found in many locations, such as adipose tissue, dermis, and bone marrow. The tropism of MSC for tumors is thought to be due to similarity in factors secreted by wounds
n3:mentions
n2:15523088
Subject Item
_:vb5045924
rdf:type
n3:Context
rdf:value
The tropism of MSC for tumors is thought to be due to similarity in factors secreted by wounds and tumors [13], substantiating the concept that tumors are “wounds that never heal” [>>14<<], [15]. It has been proposed that this tropism could be exploited by using MSC as gene-delivery vehicles for anticancer therapies, and this approach has shown promise in preclinical models [11], [12], [16]–[19]. The ability of MSC to
n3:mentions
n2:3537791
Subject Item
_:vb5045925
rdf:type
n3:Context
rdf:value
The tropism of MSC for tumors is thought to be due to similarity in factors secreted by wounds and tumors [13], substantiating the concept that tumors are “wounds that never heal” [14], [>>15<<]. It has been proposed that this tropism could be exploited by using MSC as gene-delivery vehicles for anticancer therapies, and this approach has shown promise in preclinical models [11], [12], [16]–[19]. The ability of MSC to travel to
n3:mentions
n2:4563044
Subject Item
_:vb5045926
rdf:type
n3:Context
rdf:value
It has been proposed that this tropism could be exploited by using MSC as gene-delivery vehicles for anticancer therapies, and this approach has shown promise in preclinical models [>>11<<], [12], [16]–[19].
n3:mentions
n2:12097260
Subject Item
_:vb5045927
rdf:type
n3:Context
rdf:value
It has been proposed that this tropism could be exploited by using MSC as gene-delivery vehicles for anticancer therapies, and this approach has shown promise in preclinical models [11], [>>12<<], [16]–[19].
n3:mentions
n2:15523088
Subject Item
_:vb5045928
rdf:type
n3:Context
rdf:value
It has been proposed that this tropism could be exploited by using MSC as gene-delivery vehicles for anticancer therapies, and this approach has shown promise in preclinical models [11], [12], [>>16<<]–[19]. The ability of MSC to travel to solid tumors after intravenous administration and their ability to develop myofibroblast-like characteristics under defined culture conditions [20] both suggest that TAF could be derived from MSC.
n3:mentions
n2:15833864
Subject Item
_:vb5045929
rdf:type
n3:Context
rdf:value
The ability of MSC to travel to solid tumors after intravenous administration and their ability to develop myofibroblast-like characteristics under defined culture conditions [>>20<<] both suggest that TAF could be derived from MSC.
n3:mentions
n2:10718362
Subject Item
_:vb5045930
rdf:type
n7:Section
dc:title
materials and methods
n7:contains
_:vb5045932 _:vb5045933 _:vb5045934 _:vb5045935 _:vb5045931 _:vb5045936 _:vb5045937 _:vb5045938 _:vb5045939
Subject Item
_:vb5045931
rdf:type
n3:Context
rdf:value
Murine MSC (mMSC) cell lines from C57/B6, balb/C were isolated as described previously [>>55<<] Fibroblast 3T3 cells and mMSC were cultured in alpha-MEM containing 20% FBS and 10% LPS.
n3:mentions
n2:14592819
Subject Item
_:vb5045932
rdf:type
n3:Context
rdf:value
Skov-3 tumor cells were stably transduced using a lentivirus expressing red fluorescent protein and renilla luciferase (rLuc) [>>56<<], [57].
n3:mentions
n2:18089798
Subject Item
_:vb5045933
rdf:type
n3:Context
rdf:value
Skov-3 tumor cells were stably transduced using a lentivirus expressing red fluorescent protein and renilla luciferase (rLuc) [56], [>>57<<].
n3:mentions
n2:9733856
Subject Item
_:vb5045934
rdf:type
n3:Context
rdf:value
Five minutes prior to imaging, each mouse was given an IP injection of a 100 µl injection of 40 mg/ml coelenterazine as described previously [>>56<<]. General anesthesia was then induced with 5% isoflurane (IsoSol, Medeva Pharmaceutical PA, Inc.); the mouse was placed in the light-tight heated chamber during which anesthesia was continued with 2% isoflurane introduced via nose cone.
n3:mentions
n2:18089798
Subject Item
_:vb5045935
rdf:type
n3:Context
rdf:value
In vitro tumor cell proliferation is detected by the fluorescence-based 3D TGA that noninvasively monitors tumor cell growth for eight days after cells are embedded in Cultrex BME at 3 mg/mL [>>38<<], [39]. Briefly, red fluorescent (rLUC/RFP-labeled) Skov-3 tumor cells were embedded (in triplicate) in a 100 µL plug of 3 mg/mL Cultrex BME in a black-walled, clear-bottom 96-well plate at 12,500 tumor cells (±) 3D MSC-CM, 3D MSC-CM(-GF)
n3:mentions
n2:17467167
Subject Item
_:vb5045936
rdf:type
n3:Context
rdf:value
In vitro tumor cell proliferation is detected by the fluorescence-based 3D TGA that noninvasively monitors tumor cell growth for eight days after cells are embedded in Cultrex BME at 3 mg/mL [38], [>>39<<]. Briefly, red fluorescent (rLUC/RFP-labeled) Skov-3 tumor cells were embedded (in triplicate) in a 100 µL plug of 3 mg/mL Cultrex BME in a black-walled, clear-bottom 96-well plate at 12,500 tumor cells (±) 3D MSC-CM, 3D MSC-CM(-GF) (i.e.,
n3:mentions
n2:17586727
Subject Item
_:vb5045937
rdf:type
n3:Context
rdf:value
An all inclusive description of this assay and its utility for evaluating growth rate kinetics of breast cancer cells in complex 3D tumor-like microenvironments can be found in our previously published studies [>>38<<], [39].
n3:mentions
n2:17467167
Subject Item
_:vb5045938
rdf:type
n3:Context
rdf:value
An all inclusive description of this assay and its utility for evaluating growth rate kinetics of breast cancer cells in complex 3D tumor-like microenvironments can be found in our previously published studies [38], [>>39<<].
n3:mentions
n2:17586727
Subject Item
_:vb5045939
rdf:type
n3:Context
rdf:value
GF (IL-6, EGF, HGF, VEGF, TGF-β1 and FGF) was immunoprecipitated as previously described [>>39<<]. The 3D MSC-CM was incubated with 2 µg/mL anti-GF monoclonal antibody (Mab206, Mab636, Mab294, Mab293, Mab1835 and AF233NA; R&D Systems) for 4 to 6 h at 4°C with constant rotation.
n3:mentions
n2:17586727
Subject Item
_:vb5045940
rdf:type
n7:Section
dc:title
discussion
n7:contains
_:vb5045941 _:vb5045942 _:vb5045943 _:vb5045948 _:vb5045949 _:vb5045950 _:vb5045951 _:vb5045944 _:vb5045945 _:vb5045946 _:vb5045947 _:vb5045972 _:vb5045973 _:vb5045974 _:vb5045975 _:vb5045968 _:vb5045969 _:vb5045970 _:vb5045971 _:vb5045980 _:vb5045981 _:vb5045982 _:vb5045976 _:vb5045977 _:vb5045978 _:vb5045979 _:vb5045956 _:vb5045957 _:vb5045958 _:vb5045959 _:vb5045952 _:vb5045953 _:vb5045954 _:vb5045955 _:vb5045964 _:vb5045965 _:vb5045966 _:vb5045967 _:vb5045960 _:vb5045961 _:vb5045962 _:vb5045963
Subject Item
_:vb5045941
rdf:type
n3:Context
rdf:value
The first is the bone marrow-derived progenitor population of which both hematopoietic stem cells [>>6<<] and MSC [12], [21], [22] are suggested as precursors; the second is a tissue-resident MSC population.
n3:mentions
n2:16840726
Subject Item
_:vb5045942
rdf:type
n3:Context
rdf:value
The first is the bone marrow-derived progenitor population of which both hematopoietic stem cells [6] and MSC [>>12<<], [21], [22] are suggested as precursors; the second is a tissue-resident MSC population.
n3:mentions
n2:15523088
Subject Item
_:vb5045943
rdf:type
n3:Context
rdf:value
The first is the bone marrow-derived progenitor population of which both hematopoietic stem cells [6] and MSC [12], [21], [>>22<<] are suggested as precursors; the second is a tissue-resident MSC population.
n3:mentions
n2:17675260
Subject Item
_:vb5045944
rdf:type
n3:Context
rdf:value
TAF are defined as an activated fibroblast population, which is a rich source of growth factors, such as HGF and TGFβ [>>10<<]. Activated fibroblasts form fibrovascular stromal patterns, a diverse arrangement of septa within tumors; their presence represents disordered, rapid tumor growth and can be associated with heightened tumor aggressiveness and poor
n3:mentions
n2:11962761
Subject Item
_:vb5045945
rdf:type
n3:Context
rdf:value
form fibrovascular stromal patterns, a diverse arrangement of septa within tumors; their presence represents disordered, rapid tumor growth and can be associated with heightened tumor aggressiveness and poor prognostic outcome [>>23<<]. We show the “activation” of MSC by tumor conditioned media by the increase of TAF-like surface markers ( Figure 1A ).
n3:mentions
n2:11905603
Subject Item
_:vb5045946
rdf:type
n3:Context
rdf:value
Activated fibroblasts and myofibroblasts contribute to the formation of microvascular structures and can be detected by α-SMA and desmin expression [>>24<<], [25]. Recently, published data identify pericyte characteristics by α-SMA staining within an in vivo glioma tumor model of systemically injected MSC [26]. MSC are pericytic precursors [27], and thus we hypothesize that they are
n3:mentions
n2:15010334
Subject Item
_:vb5045947
rdf:type
n3:Context
rdf:value
Activated fibroblasts and myofibroblasts contribute to the formation of microvascular structures and can be detected by α-SMA and desmin expression [24], [>>25<<]. Recently, published data identify pericyte characteristics by α-SMA staining within an in vivo glioma tumor model of systemically injected MSC [26]. MSC are pericytic precursors [27], and thus we hypothesize that they are precursors of
n3:mentions
n2:12126959
Subject Item
_:vb5045948
rdf:type
n3:Context
rdf:value
MSC are pericytic precursors [>>27<<], and thus we hypothesize that they are precursors of TAF, which are identified by pericytic, myofibroblastic and “activated” fibroblastic markers.
n3:mentions
n2:18065393
Subject Item
_:vb5045949
rdf:type
n3:Context
rdf:value
MSC represent a relatively well-defined ex vivo cell population with complex and poorly understood biology in vivo [>>28<<], [29]. MSC-based anticancer therapies represent an exciting and novel therapeutic approach, but a better understanding of how MSC home to, engraft within and ultimately have an impact on tumor behavior will be essential before we can
n3:mentions
n2:16923606
Subject Item
_:vb5045950
rdf:type
n3:Context
rdf:value
MSC represent a relatively well-defined ex vivo cell population with complex and poorly understood biology in vivo [28], [>>29<<]. MSC-based anticancer therapies represent an exciting and novel therapeutic approach, but a better understanding of how MSC home to, engraft within and ultimately have an impact on tumor behavior will be essential before we can realize
n3:mentions
n2:15145209
Subject Item
_:vb5045951
rdf:type
n3:Context
rdf:value
In those and subsequent studies, we demonstrated that MSC, administered intravenously, were able to integrate and persist within tumor stroma of pre-established human melanoma, breast cancer and glioma xenografts [>>11<<], [12], [16].
n3:mentions
n2:12097260
Subject Item
_:vb5045952
rdf:type
n3:Context
rdf:value
In those and subsequent studies, we demonstrated that MSC, administered intravenously, were able to integrate and persist within tumor stroma of pre-established human melanoma, breast cancer and glioma xenografts [11], [>>12<<], [16]. These data were confirmed in other tumor models [31], [32], most recently by Weinberg et al. [33]. We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this
n3:mentions
n2:15523088
Subject Item
_:vb5045953
rdf:type
n3:Context
rdf:value
In those and subsequent studies, we demonstrated that MSC, administered intravenously, were able to integrate and persist within tumor stroma of pre-established human melanoma, breast cancer and glioma xenografts [11], [12], [>>16<<]. These data were confirmed in other tumor models [31], [32], most recently by Weinberg et al. [33]. We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this
n3:mentions
n2:15833864
Subject Item
_:vb5045954
rdf:type
n3:Context
rdf:value
These data were confirmed in other tumor models [>>31<<], [32], most recently by Weinberg et al. [33].
n3:mentions
n2:16278396
Subject Item
_:vb5045955
rdf:type
n3:Context
rdf:value
These data were confirmed in other tumor models [31], [>>32<<], most recently by Weinberg et al. [33].
n3:mentions
n2:15048870
Subject Item
_:vb5045956
rdf:type
n3:Context
rdf:value
These data were confirmed in other tumor models [31], [32], most recently by Weinberg et al. [>>33<<]. We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this treatment had significant anti-tumor effects [11], [12], [16]. The use of cell-based delivery systems
n3:mentions
n2:17914389
Subject Item
_:vb5045957
rdf:type
n3:Context
rdf:value
We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this treatment had significant anti-tumor effects [>>11<<], [12], [16].
n3:mentions
n2:12097260
Subject Item
_:vb5045958
rdf:type
n3:Context
rdf:value
We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this treatment had significant anti-tumor effects [11], [>>12<<], [16]. The use of cell-based delivery systems such as MSC holds clinical promise and significant current research effort is focused in this area. We provide evidence herein, that the MSC has the potential to be tumor supportive. This
n3:mentions
n2:15523088
Subject Item
_:vb5045959
rdf:type
n3:Context
rdf:value
We also demonstrated that MSC could deliver therapeutic doses of interferon-beta, locally within a tumor, and demonstrated that this treatment had significant anti-tumor effects [11], [12], [>>16<<]. The use of cell-based delivery systems such as MSC holds clinical promise and significant current research effort is focused in this area. We provide evidence herein, that the MSC has the potential to be tumor supportive. This should not
n3:mentions
n2:15833864
Subject Item
_:vb5045960
rdf:type
n3:Context
rdf:value
However, in previous studies with altered tumor:MSC ratios, MSC have had adverse effects on tumor growth, prolonging the survival of the mice by hampering tumor proliferation (data not shown) [>>34<<]–[37]. In contrast to MSC inhibiting tumor progression and similar to what is described within this paper, our previous data shows that MSC can enhance the growth rate of a subpopulation of breast cancer cells in vitro and in vivo through
n3:mentions
n2:15141157
Subject Item
_:vb5045961
rdf:type
n3:Context
rdf:value
However, in previous studies with altered tumor:MSC ratios, MSC have had adverse effects on tumor growth, prolonging the survival of the mice by hampering tumor proliferation (data not shown) [34]–[>>37<<]. In contrast to MSC inhibiting tumor progression and similar to what is described within this paper, our previous data shows that MSC can enhance the growth rate of a subpopulation of breast cancer cells in vitro and in vivo through
n3:mentions
n2:14611816
Subject Item
_:vb5045962
rdf:type
n3:Context
rdf:value
and similar to what is described within this paper, our previous data shows that MSC can enhance the growth rate of a subpopulation of breast cancer cells in vitro and in vivo through paracrine interleukin-6 (IL-6) signaling events [>>38<<], [39].
n3:mentions
n2:17467167
Subject Item
_:vb5045963
rdf:type
n3:Context
rdf:value
similar to what is described within this paper, our previous data shows that MSC can enhance the growth rate of a subpopulation of breast cancer cells in vitro and in vivo through paracrine interleukin-6 (IL-6) signaling events [38], [>>39<<].
n3:mentions
n2:17586727
Subject Item
_:vb5045964
rdf:type
n3:Context
rdf:value
The first characteristic requires expression of two fibroblastic markers: FAP, which is expressed on MSC and fibroblasts [>>40<<] and FSP, a marker overexpressed in TAF as compared to normal fibroblasts [41].
n3:mentions
n2:18510677
Subject Item
_:vb5045965
rdf:type
n3:Context
rdf:value
The first characteristic requires expression of two fibroblastic markers: FAP, which is expressed on MSC and fibroblasts [40] and FSP, a marker overexpressed in TAF as compared to normal fibroblasts [>>41<<]. The expression of both markers is evident in both the systemic-MSC injected model and the admixed MSC model and furthermore not evident in the Skov-3-only IHC staining ( Figure 2A and 2B , Figure S3).
n3:mentions
n2:15950897
Subject Item
_:vb5045966
rdf:type
n3:Context
rdf:value
The second characteristic is the degree of expression of the proteins of “aggression” such as SL-1, otherwise known as MMP-3, a degradative enzyme highly expressed by fibroblasts [>>42<<] and utilized in tissue remodeling by TAF [21]. Positive staining for SL-1 was identified in Skov-3/MSC admixed tumors but Skov-3 alone as were other pathogenic-associated glycoproteins Tn-C and Tsp-1 ( Figure 2C, 2D, and 2E ).
n3:mentions
n2:16572188
Subject Item
_:vb5045967
rdf:type
n3:Context
rdf:value
Desmin, a muscle-specific, intermediate filament protein common in myofibrils [>>43<<], was expressed in huMSC derived fibroblasts in a heterogeneous pattern of distribution.
n3:mentions
n2:7049530
Subject Item
_:vb5045968
rdf:type
n3:Context
rdf:value
α-SMA positivity has been used previously to identify differentiated MSC [>>44<<]. Our data suggests that MSC do contribute to the perivascular formation within the admixed Skov-3 tumors because much of the human specific α-SMA and desmin positive staining is evident around tumor vessel structures.
n3:mentions
n2:15153614
Subject Item
_:vb5045969
rdf:type
n3:Context
rdf:value
fibrovascular septa are not the archetypal vascular endothelial cells classified by factor VIII, CD31 and CD34, but instead are networks consisting of collagen and laminin subtypes in addition to activated fibroblasts and macrophages [>>45<<]. Initial gene-expression profiles of long-term Skov-3—conditioned MSC reveal the upregulation of several laminin and collagen subtypes (data not shown); the deposition of these matrix proteins is associated with pre-vasculogenesis in
n3:mentions
n2:10487832
Subject Item
_:vb5045970
rdf:type
n3:Context
rdf:value
MSC reveal the upregulation of several laminin and collagen subtypes (data not shown); the deposition of these matrix proteins is associated with pre-vasculogenesis in preparation for the later stages including angiogenesis [>>46<<]. The TAF potential to support microvascular sprouting corroborates the in vivo tumor growth advantage of the admixed Skov-3/MSC tumors ( Figure 4A ).
n3:mentions
n2:14519385
Subject Item
_:vb5045971
rdf:type
n3:Context
rdf:value
TGF-β induces HGF expression by fibroblasts [>>47<<] but also induces the transition of fibroblasts to myofibroblasts by increasing α-SMA and Tn-C expression [48].
n3:mentions
n2:10777703
Subject Item
_:vb5045972
rdf:type
n3:Context
rdf:value
TGF-β induces HGF expression by fibroblasts [47] but also induces the transition of fibroblasts to myofibroblasts by increasing α-SMA and Tn-C expression [>>48<<]. Several adenocarcinoma tumor-microenvironment crosstalk models implicate growth factors including HGF, [49] VEGF, [50] TGF-β, and FGF [51] in the promotion/progression of tumorigenesis. The HGF/c-Met interaction plays a pivotal role in
n3:mentions
n2:15610763
Subject Item
_:vb5045973
rdf:type
n3:Context
rdf:value
Several adenocarcinoma tumor-microenvironment crosstalk models implicate growth factors including HGF, [>>49<<] VEGF, [50] TGF-β, and FGF [51] in the promotion/progression of tumorigenesis.
n3:mentions
n2:17684486
Subject Item
_:vb5045974
rdf:type
n3:Context
rdf:value
Several adenocarcinoma tumor-microenvironment crosstalk models implicate growth factors including HGF, [49] VEGF, [>>50<<] TGF-β, and FGF [51] in the promotion/progression of tumorigenesis.
n3:mentions
n2:18316602
Subject Item
_:vb5045975
rdf:type
n3:Context
rdf:value
Several adenocarcinoma tumor-microenvironment crosstalk models implicate growth factors including HGF, [49] VEGF, [50] TGF-β, and FGF [>>51<<] in the promotion/progression of tumorigenesis.
n3:mentions
n2:17637743
Subject Item
_:vb5045976
rdf:type
n3:Context
rdf:value
The HGF/c-Met interaction plays a pivotal role in cancer invasion that is mediated by the tumor stromal cell production of HGF [>>52<<], which can induce ECM degradation, tubule formation and angiogenesis [53].
n3:mentions
n2:18053801
Subject Item
_:vb5045977
rdf:type
n3:Context
rdf:value
The HGF/c-Met interaction plays a pivotal role in cancer invasion that is mediated by the tumor stromal cell production of HGF [52], which can induce ECM degradation, tubule formation and angiogenesis [>>53<<]. HGF also has the ability to transactivate the EGF receptor to induce motility [54] and reciprocally, EGF is able to stimulate HGF production [52].
n3:mentions
n2:16212809
Subject Item
_:vb5045978
rdf:type
n3:Context
rdf:value
HGF also has the ability to transactivate the EGF receptor to induce motility [>>54<<] and reciprocally, EGF is able to stimulate HGF production [52].
n3:mentions
n2:17643426
Subject Item
_:vb5045979
rdf:type
n3:Context
rdf:value
HGF also has the ability to transactivate the EGF receptor to induce motility [54] and reciprocally, EGF is able to stimulate HGF production [>>52<<].
n3:mentions
n2:18053801
Subject Item
_:vb5045980
rdf:type
n3:Context
rdf:value
Like estrogen receptor alpha (ERα)—positive breast cancer cells, on which we have previously reported [>>38<<], [39], our MSC-enhanced Skov-3 growth relies on MSC-secreted paracrine factors, such as IL-6, and not strictly on cell-cell contact.
n3:mentions
n2:17467167
Subject Item
_:vb5045981
rdf:type
n3:Context
rdf:value
Like estrogen receptor alpha (ERα)—positive breast cancer cells, on which we have previously reported [38], [>>39<<], our MSC-enhanced Skov-3 growth relies on MSC-secreted paracrine factors, such as IL-6, and not strictly on cell-cell contact.
n3:mentions
n2:17586727
Subject Item
_:vb5045982
rdf:type
n3:Context
rdf:value
of the diverse phenotype of the TAF is necessary; TAF can be matrix-synthesizing or matrix-degrading cells, they can be contractile cells (myofibroblasts), circulating precursor cells (fibrocytes), or blood vessel-associated pericytes [>>10<<], [21]. Nonetheless, TAF, in whichever form they represent in the tumor microenvironment, biologically impact tumor progression through the production of growth factors, cytokines, chemokines, matrix-degrading enzymes, and immunomodulatory
n3:mentions
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