PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of canmicrospringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
Cancer Microenviron. 2010 December; 3(1): 127–135.
Published online 2010 January 26. doi:  10.1007/s12307-010-0036-5
PMCID: PMC2990484

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Abstract

Fibroblasts play an important role in the progression, growth and spread of gastric cancers. Cancer–stroma interactions have been especially evident in the scirrhous type of gastric carcinoma. Fibroblasts are associated with the cancer progression at the primary and metastatic site. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors produced by organ-specific fibroblasts. Fibroblasts are therefore a key determinant in the malignant progression of gastric cancer and represent an important target for cancer therapies.

Keywords: Scirrhous gastric cancer, Fibroblasts, Stromal cells, Interaction, Microenvironment, Growth factor

Introduction

Tumor growth is not only determined by malignant cancer cells themselves, but also by the tumor stroma. Recently, tumor progression has been recognized as the product of an evolving crosstalk between the cancer cells and its surrounding tissue or tumor stroma [1]. Fibroblasts originally maintain the homeostasis of adjacent epithelia through the secretion of growth factors and direct mesenchymal–epithelial cell interactions. In addition, fibroblasts are associated with tumor growth and progression in various carcinomas. Moreover, cancer cells themselves may alter their adjacent stroma to form a permissive and supportive environment for tumor progression.

Scirrhous gastric carcinoma (Fig. 1a), diffusely infiltrating carcinoma, or Borrman type 4 also known as linitis plastica-type carcinoma is characterized by rapid cancer cell infiltration and proliferation accompanied by extensive stromal fibrosis [2] (Fig. 1b). Scirrhous carcinomas account for about 10% of all gastric carcinomas, and carry a worse prognosis than other types of gastric carcinoma, reflecting their rapid proliferation of cancer cells [35]. The common features of scirrhous gastric cancer include rapidly progressive invasion, and a high frequency of metastasis to the peritoneum [6]. Scirrhous gastric cancer cells proliferate with fibrosis when the cancer cells invade into the submucosa containing abundant stromal cells. These typical histological findings of rapid growth with fibrosis suggest that its development may be controlled by intercellular interactions between the scirrhous gastric cancer cells and the stromal fibroblasts. Do fibroblasts contribute to the tumor progression or suppression? This question still remains unclear [7], but data from co-cultures and in vivo experiments seem to indicate that fibroblasts have a stimulating-activity for cancer progression.

Fig. 1
Scirrhous gastric cancer. a Macroscopic findings indicate that scirrhous gastric carcinoma diffusely infiltrates a broad region of the stomach without a prominent ulceration and elevation. b Microscopical views of scirrhous gastric carcinoma have the ...

Tumor–Stroma Interactions at the Primary Site

In the early stage of carcinoma, carcinoma in situ, cancer cells are separated from stromal cells by the boundary of a basement membrane. After the tumor cells invade into the stroma, the surrounding stromal cells can affect cancer progression. Gastric cancer cells of varying differentiation have differential cancer–stroma interactions with fibroblasts.

Growth-Stimulating Interaction Between Gastric Cancer Cells and Orthotopic Fibroblasts

The interaction between gastric cancer cells and organ-specific fibroblasts is evident in vivo [8] and in vitro [6]. Co-inoculation of scirrhous gastric cancer cells with gastric fibroblasts into nude mice specifically increases tumorigenicity, in comparison to that of gastric cancer cells alone (Fig. 2a). The histological findings of the xenograft produced by co-inoculation with gastric fibroblasts show extensive stromal fibrosis with scirrhous gastric cancer cell proliferation, in comparison to that by inoculation by cancer cell alone (Fig. 2b). Furthermore, orthotopic implantation of scirrhous gastric cancer cells in stomach shows extensive fibrosis with the occasional presence of poorly differentiated adenocarcinoma cells which resembled scirrhous gastric carcinoma (Fig. 3a, b and andc).c). In contrast, the histological findings of subcutaneous xenografts of scirrhous gastric cancer cells showed medullary growth (Fig. 3d), thus suggesting that the histological findings of ectopic tumors show a difference in the histological type of original tumor from which cancer cells were derived. Conditioned medium from gastric fibroblasts stimulates the growth of gastric cancer cells. These findings suggest that the growth of scirrhous gastric cancer cells is effected by orthotopic fibroblasts. Gastric fibroblasts specifically stimulate the growth of scirrhous gastric cancer cells, but not that of well-differentiated cancer cells. Organ specificity may contribute to the histolo-pathological formation of gastric cancer, and the microenvironment inducing fibroblasts may be important for cancer development (Fig. 4).

Fig. 2
Interaction between gastric fibroblasts and scirrhous gastric cancer cells. a The tumor size achieved by the co-inoculation of scirrhous gastric cancer cells and gastric fibroblasts was much larger than that achieved by the inoculation of cancer cells ...
Fig. 3
Orthotopic implantation. a Macroscopic findings of the gastric tumor after orthotopic inoculation of gastric cancer cells showed scirrhous type carcinoma. b The orthotopic tumors showed extensive fibrosis with the presence of cancer cells which resemble ...
Fig. 4
Cancer–stroma interaction of scirrhous gastric carcinoma at primary sites. At early stage, tumor cells need to invade into submucosa beyond the mucularis mucosae. MMP-2 production from fibroblasts and loss of cell–cell adhesion by down-regulation ...

FGF-7 Produced from Gastric Fibroblasts Stimulates Proliferation of Scirrhous Gastric Cancer Cells

Interactions between scirrhous gastric cancer cells and orthotopic fibroblasts suggest that the proliferation of scirrhous gastric carcinoma is related to growth factor production by gastric fibroblasts. Among the various growth factors which are produced from fibroblasts, one of growth-stimulating factors from gastric fibroblasts that affected scirrhous gastric cancer cells is fibroblast growth factor-7 (FGF-7) [9, 10]. FGF-7, a member of the FGF family [11] also known as keratinocyte growth factor (KGF), originally was isolated from human embryonic lung fibroblasts and is produced by mesenchymal cells in various tissues. FGF-7 exerts its effect in a paracrine manner limited to epithelial cells [10], while other FGF family members also stimulate the growth of cultured endothelial cells and fibroblasts. Four members of the FGF receptor (FGFR) family, FGFR-1 (Flg), FGFR-2 (K-sam), FGFR-3, and FGFR-4, have been identified [12]. FGFR-2 is identical to the K-sam-II gene which was initially identified in an extract from the scirrhous gastric cancer cell line KATO-III. FGFR-2 is preferentially expressed in scirrhous gastric cancer. FGFR-2 mRNA is amplified from scirrhous gastric cancer cells, and the ligand FGF-7 is produced by gastric fibroblasts. FGF-7 affects the growth of scirrhous gastric cancer cells, but not that of well-differentiated adenocarcinoma cells. KGF secreted by gastric fibroblasts is important in the progression of scirrhous type of gastric cancer with K-sam-II amplification in a paracrine manner (Fig. 4).

TGFβ from Gastric Cancer Cells Stimulates the Proliferation of Fibroblasts

Orthotopic implantation of scirrhous gastric cancer cells in the stomach shows extensive fibrosis with the occasional presence of poorly differentiated adenocarcinoma cells which resembles scirrhous gastric carcinoma [13]. Scirrhous gastric cancer cells increase the proliferation of fibroblasts, but not well-differentiated adenocarcinoma cells [14]. The tumor stroma comprises most of the tumor mass in many carcinomas [15]. Its volume and composition are partly regulated by the response of the fibroblasts to the growth factors that are released by cancer cells [16] such as, TGFβ, platelet-derived growth factor (PDGF) and FGF2, all of which are key mediators of fibroblast activation and tissue fibrosis [17]. TGFβ from scirrhous gastric cancer cells stimulates the proliferation of fibroblasts. Tumor cells in scirrhous carcinoma produce more TGFβ that is key mediators of fibroblast activation, than non-scirrhous carcinoma [18, 19]. This different interaction between the two cell types and stromal cells is associated with the different biologic behaviors between the diffuse-type and intestinal-type in gastric carcinoma. Most of intestinal-type carcinoma cells proliferate in a medullary pattern, while scirrhous gastric cancer cells proliferate diffusely with extensive fibrosis [2]. This histological difference in the volume of the stroma might be determined by the response of gastric cancer cells to gastric fibroblasts. The growth-promoting factors from gastric cancer cells and organ-specific fibroblasts might mutually increase each other’s proliferation, thus resulting in the characteristic histology of gastric carcinoma (Fig. 4).

Migration-Stimulating Activity of Gastric Cancer Cells by Fibroblasts

Fibroblasts affect the invasiveness of gastric cancer cells [2023]. TGFβ produced from fibroblasts increases the invasiveness of scirrhous gastric cancer cells [24]. TGFβ is detected in a latent form in the conditioned medium from fibroblasts and in an active form in the conditioned medium from gastric cancer cells [18, 24]. The latent TGFβ is activated by proteases such as plasmin and cathepsin [25]. Most gastric cancer cells secret urokinase-type plasminogen activator (u-PA) which converts latent TGFβ to active TGFβ [26, 27]. The latent TGFβ from gastric fibroblasts and scirrhous gastric cancer cells may be activated by u-PA from scirrhous gastric cancer cells. TGFβ produced from gastric fibroblasts and cancer cells themselves affect the invasiveness of scirrhous gastric cancer cells by inducing a morphologic change to a spindle shape known as the epithelial-to-mesenchymal transition (EMT) [28]. Cancer cells undergoing the EMT develop invasive and migratory abilities [2931]. HGF is also produced by gastric fibroblasts, and affects the invasiveness of scirrhous gastric cancer cells. The c-met gene which encodes C-met as the HGF receptor is amplified more intensely in scirrhous gastric cancer than in non-scirrhous gastric cancer [5]. Since HGF is not detectable in the conditioned medium from gastric cancer cells, HGF affects the invasiveness of scirrhous gastric cancer cells in a paracrine fashion (Fig. 4). In addition to secreting growth factors that directly affect cell motility, matrix metalloproteinases (MMPs) from fibroblasts allow cancer cells to cross tissue boundaries [32, 33]. In early stage, tumor cells arised at the mucosa need to invade into submucosa beyond the mucularis mucosae. Extracellular matrix degradation and loss of cell–cell adhesion might facilitate the tumor invasion. MMP-2 produced from fibroblasts is activated by MT1-MMP expressed on gastric cancer cells [34]. MMP2 from the stromal cells may affect cancer progression in a paracrine manner, even though cancer cells are separated from stromal cells by the basement membrane. Moreover, down-regulation of E-cadherin frequently found in diffuse-type gastric carcinoma by methylation and mutations may be involved in tumor invasion [35]. Also, loss of heterozygosity at chromosome 18q12, on which cell–cell adhesion molecule Desmoglein-2 exists, is frequent in diffuse-type gastric cancer [36, 37].

Cancer–Stromal Interactions at Peritoneal Metastatic Sites

Peritoneal metastasis is the most frequent type of metastasis in gastric cancer. The peritoneum is composed of a superficial monolayer of mesothelial cells and submesothelial stromal tissue. The peritoneal metastatic sites also offer cancer–stromal interactions [20]. Fibroblasts at peritoneal metastatic sites seem to be conducive to tumor progression.

Adhesion of Cancer Cells to the Peritoneum

The adhesion of cancer cells to the peritoneum during peritoneal metastatic spread is an important step for metastasis. Cancer cells initially adhere to the mesothelial cells, and then adhere to the submesothelial connective tissue after the exfoliation of the mesothelial cells. Since peritoneal mesothelial cells express hyaluronic acid on their cell surface, the adhesion molecule CD44 expressed on the cancer cells mediates the binding of cancer cells to hyaluronic acid on mesothelial cells [38] (Fig. 5). Stromal fibroblasts up-regulate the CD44 expression of gastric cancer cells via TGFβ signaling, thus resulting in the stimulation of the adhesion ability of scirrhous gastric cancer cells to the mesothelium [39]. The adhesion of cancer cells to the submesothelial components is also an important process in peritoneal dissemination. The submesothelial matrix is mainly composed of laminin, fibronectin, type IV collagen and type I collagen. Among the family of integrins, α2β1- and α3β1-integrin on cancer cells are key molecules to adhere to these submesothelial components [12, 40] (Fig. 5). Gastric cancer cells leaving the primary tumor are exposed to low oxygen levels in the peritoneal cavity [41]. The binding ability of scirrhous gastric cancer cells is increased by hypoxic (1% O2) conditions in comparison to normoxic (21% O2) conditions. TGFβ increases the adhesion ability and α2-, α3-, and α5-integrin expression of gastric cancer cells under hypoxia. A hypoxic environment promotes adhesion of scirrhous gastric cancer cells to the peritoneum. The upregulation of α2-, α3-, and α5-integrin by TGFβ under hypoxic conditions may be one of the mechanisms responsible for the high metastatic potential of scirrhous gastric cancer cells. The adhesion polypeptides, Tyr-Ile-Gly-Ser-Arg (YIGSR) and Arg-Gly-Asp (RGD), are the cell binding domain of the extra-cellular matrix (ECM) [42, 43], and these peptides interfere with cell binding by integrins [44]. The adhesion polypeptides, YIGSR and RGD inhibit the adhesion ability of β1-integrin on gastric cancer cells. The peritoneal injection of adhesion polypeptides may be useful for the prevention of peritoneal metastasis [45].

Fig. 5
Cancer–stroma interactions in scirrhous gastric carcinoma at peritoneal metastatic sites. Cancer cells free in the abdominal cavity initially adhere to hyaluronic acid on the mesothelial cells mediated by CD44 on the cancer cells. Thereafter, ...

Cancer Cells Modulate Their Stromal Environment—“Seed and Soil”

Cancer cells usually generate a supportive microenvironment by producing stroma-modulating growth factors. These include the FGF family, vascular endothelial growth factor (VEGF) family, PDGF, epidermal growth factor receptor (EGFR) ligands, interleukins, TGFβ. These factors activate surrounding stromal cell types, such as fibroblasts, leading to the secretion of additional growth factors and proteases. The scirrhous gastric cancer cells stimulate the proliferation of peritoneal fibroblasts probably by TGFβ while, in contrast, well-differentiated adenocarcinoma cells do not [14]. The histological findings of peritoneums with carcinomatous peritonitis show extensive proliferation of fibroblasts [46]. Fibrosis of the peritoneum also is recognized in areas without cancer cell infiltration. Tumorigenicity following intraperitoneal inoculation of scirrhous gastric cancer cells is increased in mice with pre-existing peritoneal fibrosis [46]. The peritoneal fibrosis induced by factors from cancer cells stimulates the migratory capability of scirrhous gastric cancer cells into the peritoneum. In addition, peritoneal fibrosis decreases the anti-metastasis activity of the mesothelial cells [14]. Peritoneal fibroblasts might play an important role in peritoneal implantation of scirrhous gastric cancer cells, similar to the fibroblasts in the primary tumor. Clinical observations suggest that certain tumors consistently metastasize to particular organs. Paget has explained this phenomenon by the “seed and soil” theory [47, 48]; metastases occurs when some tumor cells “seed” only live and grow in a congenial environment “soil” [49]. Peritoneal fibrosis induced by cancer cells may create a congenial environment “soil” for peritoneal metastases of scirrhous gastric carcinoma (Fig. 5).

HGF and TGFβ Affect Mesothelial Cell Morphology

Mesothelial cell monolayers prevent infiltration of cancer cells into the peritoneum. TGFβ from gastric cancer cells causes morphological changes in mesothelial cells and may thus be closely associated with peritoneal dissemination [50]. Moreover, mesothelial cells become hemispherical and exfoliate from the peritoneum. Mesothelial cells exposed to fibroblasts proliferation become hemispherical and separated from each other, while unexposed mesothelium remains as a flat monolayer. Cultured-mesothelial cells round up or exhibit a fibroblast-like shape following the addition of peritoneal fibroblasts. Morphological changes are stimulated in mesothelial cells not only by cancer cells, but also by host fibroblasts [46]. HGF produced by peritoneal fibroblasts affect the morphology of mesothelial cells in monolayers so that the resulting environment becomes compatible with the peritoneal dissemination of cancer cells [51]. Peritoneal fibroblasts may thus exert some effects on mesothelial cells that precede metastasis (Fig. 5).

Tumor-Activated Fibroblasts

Most of fibroblasts used in the above studies are derived from cancer tissues. Fibroblasts within the tumor stroma, known as carcinoma-associated fibroblasts (CAFs), may acquire a modified phenotype [52, 53]. A further link between growth factors and CAFs in tumor initiation is indicated by a series of studies comparing the effect of normal fibroblasts and of CAFs isolated from the primary tumor site [54]. In culture, the phenotypic features of CAFs can be induced by various growth factors such as TGFβ, which mediates fibroblast activation. TGFβ-induced chemotaxis of fibroblasts and their transdifferentiation into activated smooth-muscle reactive fibroblasts, termed myofibroblasts [55]. Fibroblasts could become activated and further modified when cultured in vitro. Therefore, the role of normal resident fibroblasts in cancer progression remains unclear. Additional studies are needed to determine whether CAFs represent a unique fibroblast phenotype in comparison to normal host-fibroblasts. Furthermore, targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that requires further study.

Therapies to Target the Cancer–Stromal Interactions

Recent advances in the understanding of tumor–stroma interactions have elucidated various molecules which are characteristic of the cancer environment. The elucidation of tumor–stroma molecular interactions could provide a new targeted cancer therapy. Since the mechanisms that regulate fibroblast activation and their accumulation in cancer are becoming to be clear, fibroblasts might serve as novel therapeutic targets in cancer. Such therapies can be given alone or in combination with chemotherapy, radiation or surgery. Scirrhous gastric carcinoma shows a poor 5-year survival rate from 10% to 15% [56]. Various types of therapy, including chemotherapy, hormonal therapy, hyperthermia, and immunotherapy, have been tested for effectiveness in scirrhous gastric carcinoma at advance stage, but none have been unsatisfactory [57]. Accordingly, new therapies based on the characteristic cancer–stromal interactions in scirrhous gastric cancer have been urgently sought.

Tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid), a drug used clinically for the treatment of excessive proliferation of fibroblasts, decreases gastric carcinoma growth and induces cancer cell apoptosis through its effect in blocking the growth-interactions between fibroblasts and scirrhous gastric cancer cells [34]. Tranilast inhibits not only the proliferation of fibroblasts but also the release of growth-promoting factors from fibroblasts and cancer cells, and then down-regulates the growth-interactions between fibroblasts and cancer cells [58]. In addition, the combination treatment with Tranilast and cisplatin decreases the xenografted tumor size, fibrosis, and mitosis, and increases apoptosis [59]. Furthermore, Tranilast suppresses the invasion-stimulating ability of fibroblasts by inhibiting the production of MMP-2 and TGFβ from fibroblasts [60]. Tranilast may be a promising new drug to inhibit the interaction of proliferation and invasion between fibroblasts and scirrhous gastric cancer cells [58].

Cyclooxygenase (COX), a molecular target of NSAIDs, has two isoforms, COX-1 and COX-2. While COX-1 is expressed constitutively at a constant rate, COX-2 expression is regulated by various factors. In particular, COX-2 is overexpressed in stromal cells such as macrophages [61] and fibroblasts [62, 63] in various tumors. COX-2 produced by stromal cells stimulates proliferation and invasion of human carcinoma by stimulating stromal production of various cytokines [64]. The overexpression of COX-2 has been linked to the development of various types of human cancers [65, 66]. Several reports have indicated that COX-2 affects the invasiveness of cancer cells [6769]. Gastric fibroblasts stimulate the invasiveness of scirrhous gastric cancer cells, while a selective COX-2 inhibitor, JTE-522, decreases HGF production from gastric fibroblasts by suppression of PGE2 productions, thus resulting in decreased invasion ability of gastric cancer cells [62, 70]. Moreover, JTE-522 down-regulates FGF-7 production from gastric fibroblasts, thus resulting in the inhibition of paracrine epithelial–mesenchymal interactions of between scirrhous gastric cancer cells and gastric fibroblasts [71].

FGFR-2/K-samII, a tyrosine kinase growth factor receptor, is overexpressed on scirrhous gastric cancer cells [7275]. The secretion of FGF-7; a ligand of FGFR-2, by gastric fibroblasts is likely to contribute in a paracrine manner to the remarkable cell proliferation seen in scirrhous gastric cancer with FGFR-2/K-samII amplification [9]. Tyrosine kinase inhibitors act on the cytosolic ATP-binding domain of such receptors by inhibiting autophosphorylation. A major downstream signaling route of the FGF-R family is via the MAPK pathway. Ki23057, a newly developed small molecule acting FGFR-2/K-samII inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase [76]. Ki23057 decreases the proliferation of scirrhous cancer cells by inhibiting the phosphorylation of FGFR-2/K-samII, thus resulting in an increase of apoptosis [77]. The oral administration of Ki23057 prolongs the survival of mice with peritoneal metastasis of scirrhous cancer. The combined administration of S1 and Ki23057 decreases orthotopic tumors as well as LN metastasis more effectively than S1 alone [78, 79]. FGFR-2 phosphorylation inhibitor appears therapeutically promising in scirrhous gastric carcinoma with K-samII amplification.

TGFβ is secreted by a range of tumor cells [7] and mediates the interaction of cancer cells with stromal fibroblasts [1]. The administration of TGFβ receptor (TGFβ-R) inhibitor, A-77, improves the prognosis of the mice with peritoneal dissemination [80]. A-77 administration reduces the fibrosis and causes the medullary formation of cancer cells in vivo. The invasiveness of scirrhous gastric cancer cells is significantly increased in a co-culture with fibroblasts, and A-77 significantly decreases the invasion ability of scirrhous gastric cancer cells. A-77 is therefore suggested to inhibit the invasion ability of cancer cells by suppressing the intercellular interaction between the scirrhous gastric cancer cells and surrounding fibroblasts. A-77 decreases the expression of α2-, α3- and α5-integrin in gastric cancer cells. A-77 decreases the growth of fibroblast, and invasion-stimulating activity of fibroblasts on cancer cells. A-77 is thus considered to be useful for inhibiting the peritoneal dissemination of scirrhous gastric carcinoma. TGFβ seems to stimulate tumor progression in the tumor–stroma interaction, while the specific role of TGFβ in tumor progression is still controversial [81]. TGFβ probably functions as a tumor suppressor before the initiation of cancer, and during the early stages of carcinogenesis. In contrast, during the advanced stages of cancer, TGFβ signaling promotes cancer progression and metastasis [82]. Additional studies are needed to examine the clinical effect of TGFβ-R inhibitor on the progression of gastric carcinoma at both the early and advanced stages.

In conclusion, stromal fibroblasts have been proven to play an important role in the progression of scirrhous gastric carcinomas. The tumor–stroma interaction might therefore be a promising target for cancer therapy in gastric cancer, especially in the scirrhous type of cancer.

References

1. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401. doi: 10.1038/nrc1877. [PubMed] [Cross Ref]
2. Japanese Gastric Cancer A Japanese classification of gastric carcinoma—2nd English Edition. Gastric Cancer. 1998;1(1):10–24. doi: 10.1007/PL00011681. [PubMed] [Cross Ref]
3. Ikeguchi M, Miyake T, Matsunaga T, et al. Recent results of therapy for scirrhous gastric cancer. Surg Today. 2009;39(4):290–294. doi: 10.1007/s00595-008-3860-1. [PubMed] [Cross Ref]
4. Otsuji E, Kuriu Y, Okamoto K, et al. Outcome of surgical treatment for patients with scirrhous carcinoma of the stomach. Am J Surg. 2004;188(3):327–332. doi: 10.1016/j.amjsurg.2004.06.010. [PubMed] [Cross Ref]
5. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;157:327–349. [PubMed]
6. Yashiro M, Chung YS, Kubo T, et al. Differential responses of scirrhous and well-differentiated gastric cancer cells to orthotopic fibroblasts. Br J Cancer. 1996;74(7):1096–1103. [PMC free article] [PubMed]
7. Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4(11):839–849. doi: 10.1038/nrc1477. [PubMed] [Cross Ref]
8. Yashiro M, Chung YS, Sowa M. Role of orthotopic fibroblasts in the development of scirrhous gastric carcinoma. Jpn J Cancer Res. 1994;85(9):883–886. [PubMed]
9. Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res. 2003;63(24):8848–8852. [PubMed]
10. Shaoul R, Eliahu L, Sher I, et al. Elevated expression of FGF7 protein is common in human gastric diseases. Biochem Biophys Res Commun. 2006;350(4):825–833. doi: 10.1016/j.bbrc.2006.08.198. [PubMed] [Cross Ref]
11. Katoh M, Katoh M. FGF signaling network in the gastrointestinal tract (review) Int J Oncol. 2006;29(1):163–168. [PubMed]
12. Katoh M. Cancer genomics and genetics of FGFR2 (Review) Int J Oncol. 2008;33(2):233–237. [PubMed]
13. Takemura S, Yashiro M, Sunami T, et al. Novel models for human scirrhous gastric carcinoma in vivo. Cancer science. 2004;95(11):893–900. doi: 10.1111/j.1349-7006.2004.tb02199.x. [PubMed] [Cross Ref]
14. Yashiro M, Chung YS, Nishimura S, et al. Fibrosis in the peritoneum induced by scirrhous gastric cancer cells may act as “soil” for peritoneal dissemination. Cancer. 1996;77(8 Suppl):1668–1675. [PubMed]
15. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996;76(1):69–125. [PubMed]
16. Tahara E. Abnormal growth factor/cytokine network in gastric cancer. Cancer Microenviron. 2008;1(1):85–91. doi: 10.1007/s12307-008-0008-1. [PMC free article] [PubMed] [Cross Ref]
17. Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001;264(1):169–184. doi: 10.1006/excr.2000.5133. [PubMed] [Cross Ref]
18. Mahara K, Kato J, Terui T, et al. Transforming growth factor beta 1 secreted from scirrhous gastric cancer cells is associated with excess collagen deposition in the tissue. Br J Cancer. 1994;69(4):777–783. [PMC free article] [PubMed]
19. Yoshida K, Yokozaki H, Niimoto M, et al. Expression of TGF-beta and procollagen type I and type III in human gastric carcinomas. Int J Cancer. 1989;44(3):394–398. doi: 10.1002/ijc.2910440303. [PubMed] [Cross Ref]
20. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239–252. doi: 10.1038/nrc2618. [PubMed] [Cross Ref]
21. Cat B, Stuhlmann D, Steinbrenner H, et al. Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species. J Cell Sci. 2006;119(Pt 13):2727–2738. doi: 10.1242/jcs.03011. [PubMed] [Cross Ref]
22. Wever O, Demetter P, Mareel M, et al. Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer. 2008;123(10):2229–2238. doi: 10.1002/ijc.23925. [PubMed] [Cross Ref]
23. Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003;200(4):429–447. doi: 10.1002/path.1398. [PubMed] [Cross Ref]
24. Inoue T, Chung YS, Yashiro M, et al. Transforming growth factor-beta and hepatocyte growth factor produced by gastric fibroblasts stimulate the invasiveness of scirrhous gastric cancer cells. Jpn J Cancer Res. 1997;88(2):152–159. [PubMed]
25. George SJ, Johnson JL, Smith MA, et al. Transforming growth factor-beta is activated by plasmin and inhibits smooth muscle cell death in human saphenous vein. J Vasc Res. 2005;42(3):247–254. doi: 10.1159/000085657. [PubMed] [Cross Ref]
26. Duffy MJ, Maguire TM, McDermott EW, et al. Urokinase plasminogen activator: a prognostic marker in multiple types of cancer. J Surg Oncol. 1999;71(2):130–135. doi: 10.1002/(SICI)1096-9098(199906)71:2<130::AID-JSO14>3.0.CO;2-9. [PubMed] [Cross Ref]
27. Herszenyi L, Plebani M, Carraro P, et al. Proteases in gastrointestinal neoplastic diseases. Clin Chim Acta. 2000;291(2):171–187. doi: 10.1016/S0009-8981(99)00227-2. [PubMed] [Cross Ref]
28. Zeisberg EM, Potenta S, Xie L, et al. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67(21):10123–10128. doi: 10.1158/0008-5472.CAN-07-3127. [PubMed] [Cross Ref]
29. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–454. doi: 10.1038/nrc822. [PubMed] [Cross Ref]
30. Kalluri R, Neilson EG. Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776–1784. [PMC free article] [PubMed]
31. Siegel PM, Massague J. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer. 2003;3(11):807–821. doi: 10.1038/nrc1208. [PubMed] [Cross Ref]
32. Stetler-Stevenson WG, Aznavoorian S, Liotta LA. Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol. 1993;9:541–573. doi: 10.1146/annurev.cb.09.110193.002545. [PubMed] [Cross Ref]
33. Boire A, Covic L, Agarwal A, et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005;120(3):303–313. doi: 10.1016/j.cell.2004.12.018. [PubMed] [Cross Ref]
34. Yashiro M, Chung YS, Sowa M. Tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) down-regulates the growth of scirrhous gastric cancer. Anticancer Res. 1997;17(2A):895–900. [PubMed]
35. Humar B, Guilford P. Hereditary diffuse gastric cancer: a manifestation of lost cell polarity. Cancer science. 2009;100(7):1151–1157. doi: 10.1111/j.1349-7006.2009.01163.x. [PubMed] [Cross Ref]
36. Yashiro M, Nishioka N, Hirakawa K. Decreased expression of the adhesion molecule desmoglein-2 is associated with diffuse-type gastric carcinoma. Eur J Cancer. 2006;42(14):2397–2403. doi: 10.1016/j.ejca.2006.03.024. [PubMed] [Cross Ref]
37. Nishioka N, Yashiro M, Inoue T, et al. A candidate tumor suppressor locus for scirrhous gastric cancer at chromosome 18q 12.2. Int J Oncol. 2001;18(2):317–322. [PubMed]
38. Nishimura S, Chung YS, Yashiro M, et al. CD44H plays an important role in peritoneal dissemination of scirrhous gastric cancer cells. Jpn J Cancer Res. 1996;87(12):1235–1244. [PubMed]
39. Koyama T, Yashiro M, Inoue T, et al. TGF-beta1 secreted by gastric fibroblasts up-regulates CD44H expression and stimulates the peritoneal metastatic ability of scirrhous gastric cancer cells. Int J Oncol. 2000;16(2):355–362. [PubMed]
40. Nishimura S, Chung YS, Yashiro M, et al. Role of alpha 2 beta 1- and alpha 3 beta 1-integrin in the peritoneal implantation of scirrhous gastric carcinoma. Br J Cancer. 1996;74(9):1406–1412. [PMC free article] [PubMed]
41. Kizaka-Kondoh S, Itasaka S, Zeng L, et al. Selective killing of hypoxia-inducible factor-1-active cells improves survival in a mouse model of invasive and metastatic pancreatic cancer. Clin Cancer Res. 2009;15(10):3433–3441. doi: 10.1158/1078-0432.CCR-08-2267. [PubMed] [Cross Ref]
42. Graf J, Iwamoto Y, Sasaki M, et al. Identification of an amino acid sequence in laminin mediating cell attachment, chemotaxis, and receptor binding. Cell. 1987;48(6):989–996. doi: 10.1016/0092-8674(87)90707-0. [PubMed] [Cross Ref]
43. Akiyama SK, Yamada SS, Chen WT, et al. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol. 1989;109(2):863–875. doi: 10.1083/jcb.109.2.863. [PMC free article] [PubMed] [Cross Ref]
44. Iwamoto Y, Robey FA, Graf J, et al. YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation. Science. 1987;238(4830):1132–1134. doi: 10.1126/science.2961059. [PubMed] [Cross Ref]
45. Matsuoka T, Hirakawa K, Chung YS, et al. Adhesion polypeptides are useful for the prevention of peritoneal dissemination of gastric cancer. Clin Exp Metastasis. 1998;16(4):381–388. doi: 10.1023/A:1006573732238. [PubMed] [Cross Ref]
46. Yashiro M, Chung YS, Nishimura S, et al. Peritoneal metastatic model for human scirrhous gastric carcinoma in nude mice. Clin Exp Metastasis. 1996;14(1):43–54. doi: 10.1007/BF00157685. [PubMed] [Cross Ref]
47. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101. [PubMed]
48. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–458. doi: 10.1038/nrc1098. [PubMed] [Cross Ref]
49. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9(4):285–293. doi: 10.1038/nrc2621. [PubMed] [Cross Ref]
50. Nishimura S, Hirakawa-Chung KY, Yashiro M, et al. TGF-beta1 produced by gastric cancer cells affects mesothelial cell morphology in peritoneal dissemination. Int J Oncol. 1998;12(4):847–851. [PubMed]
51. Yashiro M, Chung YS, Inoue T, et al. Hepatocyte growth factor (HGF) produced by peritoneal fibroblasts may affect mesothelial cell morphology and promote peritoneal dissemination. Int J Cancer. 1996;67(2):289–293. doi: 10.1002/(SICI)1097-0215(19960717)67:2<289::AID-IJC22>3.0.CO;2-5. [PubMed] [Cross Ref]
52. Schor SL, Schor AM, Grey AM, et al. Foetal and cancer patient fibroblasts produce an autocrine migration-stimulating factor not made by normal adult cells. J Cell Sci. 1988;90(Pt 3):391–399. [PubMed]
53. Durning P, Schor SL, Sellwood RA. Fibroblasts from patients with breast cancer show abnormal migratory behaviour in vitro. Lancet. 1984;2(8408):890–892. doi: 10.1016/S0140-6736(84)90653-6. [PubMed] [Cross Ref]
54. Olumi AF, Grossfeld GD, Hayward SW, et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59(19):5002–5011. [PubMed]
55. Lewis MP, Lygoe KA, Nystrom ML, et al. Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer. 2004;90(4):822–832. doi: 10.1038/sj.bjc.6601611. [PMC free article] [PubMed] [Cross Ref]
56. Liu Y, Yoshimura K, Yamaguchi N, et al. Causation of Borrmann type 4 gastric cancer: heritable factors or environmental factors? Gastric Cancer. 2003;6(1):17–23. doi: 10.1007/s101200300002. [PubMed] [Cross Ref]
57. Samel S, Singal A, Becker H, et al. Problems with intraoperative hyperthermic peritoneal chemotherapy for advanced gastric cancer. Eur J Surg Oncol. 2000;26(3):222–226. doi: 10.1053/ejso.1999.0780. [PubMed] [Cross Ref]
58. Prud’homme GJ. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest. 2007;87(11):1077–1091. doi: 10.1038/labinvest.3700669. [PubMed] [Cross Ref]
59. Murahashi K, Yashiro M, Inoue T, et al. Tranilast and cisplatin as an experimental combination therapy for scirrhous gastric cancer. Int J Oncol. 1998;13(6):1235–1240. [PubMed]
60. Yashiro M, Murahashi K, Matsuoka T, et al. Tranilast (N-3,4-dimethoxycinamoyl anthranilic acid): a novel inhibitor of invasion-stimulating interaction between gastric cancer cells and orthotopic fibroblasts. Anticancer Res. 2003;23(5A):3899–3904. [PubMed]
61. Iwata C, Kano MR, Komuro A, et al. Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res. 2007;67(21):10181–10189. doi: 10.1158/0008-5472.CAN-07-2366. [PubMed] [Cross Ref]
62. Tendo M, Yashiro M, Nakazawa K, et al. Inhibitory effect of a selective cyclooxygenase inhibitor on the invasion-stimulating activity of orthotopic fibroblasts for scirrhous gastric cancer cells. Cancer science. 2005;96(7):451–455. doi: 10.1111/j.1349-7006.2005.00066.x. [PubMed] [Cross Ref]
63. Sonoshita M, Takaku K, Oshima M, et al. Cyclooxygenase-2 expression in fibroblasts and endothelial cells of intestinal polyps. Cancer Res. 2002;62(23):6846–6849. [PubMed]
64. Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2) Cell. 1996;87(5):803–809. doi: 10.1016/S0092-8674(00)81988-1. [PubMed] [Cross Ref]
65. Williams CS, Tsujii M, Reese J, et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest. 2000;105(11):1589–1594. doi: 10.1172/JCI9621. [PMC free article] [PubMed] [Cross Ref]
66. Sawaoka H, Kawano S, Tsuji S, et al. Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am J Physiol. 1998;274(6 Pt 1):G1061–G1067. [PubMed]
67. Chen WS, Wei SJ, Liu JM, et al. Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer. 2001;91(6):894–899. doi: 10.1002/1097-0215(200102)9999:9999<894::AID-IJC1146>3.0.CO;2-#. [PubMed] [Cross Ref]
68. Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93(5):705–716. doi: 10.1016/S0092-8674(00)81433-6. [PubMed] [Cross Ref]
69. Kamei D, Murakami M, Nakatani Y, et al. Potential role of microsomal prostaglandin E synthase-1 in tumorigenesis. J Biol Chem. 2003;278(21):19396–19405. doi: 10.1074/jbc.M213290200. [PubMed] [Cross Ref]
70. Tendo M, Yashiro M, Nakazawa K, et al. A synergic inhibitory-effect of combination with selective cyclooxygenase-2 inhibitor and S-1 on the peritoneal metastasis for scirrhous gastric cancer cells. Cancer Lett. 2006;244(2):247–251. doi: 10.1016/j.canlet.2005.12.019. [PubMed] [Cross Ref]
71. Yashiro M, Nakazawa K, Tendo M, et al. Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial–mesenchymal interactions of growth in scirrhous gastric carcinoma. Int J Cancer. 2007;120(3):686–693. doi: 10.1002/ijc.22329. [PubMed] [Cross Ref]
72. Hattori Y, Itoh H, Uchino S, et al. Immunohistochemical detection of K-sam protein in stomach cancer. Clin Cancer Res. 1996;2(8):1373–1381. [PubMed]
73. Toyokawa T, Yashiro M, Hirakawa K. Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma. Oncol Rep. 2009;21(4):875–880. [PubMed]
74. Hattori Y, Odagiri H, Nakatani H, et al. K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci U S A. 1990;87(15):5983–5987. doi: 10.1073/pnas.87.15.5983. [PubMed] [Cross Ref]
75. Katoh M, Hattori Y, Sasaki H, et al. K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase. Proc Natl Acad Sci U S A. 1992;89(7):2960–2964. doi: 10.1073/pnas.89.7.2960. [PubMed] [Cross Ref]
76. Shimizu T, Fujiwara Y, Osawa T, et al. Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors. Bioorg Med Chem Lett. 2004;14(4):875–879. doi: 10.1016/j.bmcl.2003.12.019. [PubMed] [Cross Ref]
77. Nakamura K, Yashiro M, Matsuoka T, et al. A novel molecular targeting compound as K-samII/FGF-R2 phosphorylation inhibitor, Ki23057, for Scirrhous gastric cancer. Gastroenterology. 2006;131(5):1530–1541. doi: 10.1053/j.gastro.2006.08.030. [PubMed] [Cross Ref]
78. Yashiro M, Shinto O, Nakamura K, et al. Synergistic anti-tumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int J Cancer. 2009;126(4):1004–1016. [PubMed]
79. Yashiro M, Shinto O, Nakamura K, et al. Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model. Br J Cancer. 2009;101(7):1100–1106. doi: 10.1038/sj.bjc.6605296. [PMC free article] [PubMed] [Cross Ref]
80. Kawajiri H, Yashiro M, Shinto O, et al. A novel transforming growth factor beta receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma. Clin Cancer Res. 2008;14(9):2850–2860. doi: 10.1158/1078-0432.CCR-07-1634. [PubMed] [Cross Ref]
81. Bierie B, Moses HL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–520. doi: 10.1038/nrc1926. [PubMed] [Cross Ref]
82. Akhurst RJ. TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest. 2002;109(12):1533–1536. [PMC free article] [PubMed]

Articles from Cancer Microenvironment are provided here courtesy of Springer Science+Business Media B.V.