Survey Part- A ] Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment

Independent role of Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment:


e) Churg-Strauss syndrome (CSS): is a systemic disease that shows marked eosinophilia along with eosinophil infiltration in the tissue. Prolonged eosinophil survival plays an important role in the pathogenesis of CSS(1), which is also invole development of lipoma, a very rare benign tumor of the tracheobronchial tree(2).

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase, and its ligand is collagen. DDR1 was expressed in human leukocytes and fibroblasts, and it plays an important role in leukocyte cytokine production and fibroblast survival in an NF-kappaB-dependent manner, as well as (DDR1) contributes to the eosinophil survival in the tissue microenvironment of CSS and that it might be involved in the development of CSS.

References:
1 Matsuyama W etal Discoidin domain receptor 1 contributes to eosinophil survival in an NF-kappaB-dependent manner in Churg-Strauss syndrome Blood. 2007 Jan 1;109(1):22-30..

2 Ergan-Arsava B etal Endobronchial lipoma in a patient with Churg-Strauss syndrome Thorac Cardiovasc Surg. 2006 Jun;54(4):283-5.


f) inducible fibroblast growth factor receptor-1 (iFGFR1):
Using an inducible transgenic mouse model of preneoplastic progression in the mammary gland, the authors discovered that activation of inducible fibroblast growth factor receptor-1 (iFGFR1) in the mammary epithelium rapidly increased the expression of several genes involved in the inflammatory response, which induced recruitment of macrophages (responsible for preneoplastic progression) to the epithelium and continued association with the alveolar hyperplasias that developed following long-term activation. Further more studies also showed that iFGFR1-induced expression of the macrophage chemoattractant osteopontin was required for macrophage recruitment in vitro.

Reference:
Schwertfeger KL etal A critical role for the inflammatory response in a mouse model of preneoplastic progression Cancer Res. 2006 Jun 1;66(11):5676-85


g) isozyme of 6-phosphofructo-2 kinase (iPFK-2):

Tumor cells maintain an especially high glycolytic rate to supply the anabolic precursors essential for de novo nucleotide synthesis. We recently cloned an inducible isozyme of 6-phosphofructo-2 kinase (iPFK-2) that bears an oncogene-like regulatory element in its mRNA and functions to produce fructose-2,6-bisphosphate, which is a powerful allosteric activator of glycolysis. Rapidly proliferating cancer cells constitutively express iPFK-2 in vitro, and inhibition of iPFK-2 expression decreases tumor growth in experimental animal models.

In particular, iPFK-2 expression was found to be markedly elevated in multiple aggressive primary neoplasms, including colon, breast, ovarian, and thyroid carcinomas. iPFK-2 mRNA and protein expression were induced by hypoxia in cultured human colon adenocarcinoma cells, and an examination of normal lung fibroblasts showed that iPFK-2 and fructose-2,6-bisphosphate levels increased specifically during the S phase of the cell cycle. These data indicate that iPFK-2 is abundantly expressed in human tumors in situ and may serve as an essential regulator of glycolysis during cell cycle progression and growth in an hypoxic microenvironment.


Reference:
Atsumi T etal High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers Cancer Res. 2002 Oct 15;62(20):5881-7



-> to be continued..;becasue of likes to do some correlated studies---<-

Survey Part- A ] Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment

d) Serine/threonine protein kinases: AGC group: (AKT family - AKT; RAC serine/threonine-protein kinase) and associated proteins:

The stromal microenvironment influences many steps of tumor progression through the elaboration of signals from myofibroblasts. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway transduces signals initiated by growth factors and is involved in colonic epithelial proliferation. Utilizing a novel proteomic approach, the authors have identify distinct protein profiles in myofibroblasts of polyps compared with stromal cells of normal mucosa. Moreover, myofibroblasts can stimulate indirectly PI3K activity and enhance colon cancer cell proliferation. These findings suggest that targeted therapy to signaling pathways in myofibroblasts may be useful in colorectal cancer chemoprevention and possible treatment.

hint: polyp myofibroblasts enhanced proliferation of the cancer cells to a greater extent than normal myofibroblasts.(1)

To assess microenvironment-mediated survival signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk-, with and without an agonistic antibody to CD40. Spontaneous apoptosis was associated with the loss of Akt and NF-kappaB activities. Interactions with fibroblasts sustained a basal level of Akt and NF-kappaB activities, which was dependent on phosphatidylinositol-3 kinase (PI3K). Constitutive activity of the PI3K pathway in B-CLL cells when cultured with fibroblasts prevented the downregulation of the prosurvival Bcl-2 family protein Bcl-xL and the caspase inhibitor proteins FLIPL and XIAP, and consequently caspase-3 activation and apoptosis. CD40 crosslinking in B-CLL cells did not further prevent murine fibroblasts-mediated apoptosis but induced cell proliferation, which was associated with an increase of Akt and NF-kappaB activation compared with cells cultured with fibroblasts alone. The PI3K pathway seems to play a pivotal role in B-CLL cell survival and growth.(2)


1Chen AL etal Proteomic analysis of colonic myofibroblasts and effect on colon cancer cell proliferation
Surgery. 2005 Aug;138(2):382-90

2Cuní S etal A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells Leukemia. 2004 Aug;18(8):1391-400


For quick references/basic-facts:

Tsai KK etal Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment Cancer Res. 2005 Aug 1;65(15):6734-44

Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the alpha6beta4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions.

Survey Part- A ] Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment

c) Serine/threonine protein kinases: CMGC group(MAPK family - ERK1_2; extracellular signal-regulated kinase ½) and associated proteins:

i) Cancer cell migration:
Protease-activated receptors (PAR) are G protein-coupled receptors that function as cell-surface sensors for coagulant proteases, as well as other proteases associated with the tumor microenvironment. PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2. PAR1 has been implicated in tumor cell growth, migration, and invasion whereas the function of PAR2 in these processes is largely unknown.

Studies with siRNA strongly suggest that PAR2 is critical for MDA-MB-231 and BT549 breast cancer cell migration and invasion towards NIH 3T3 fibroblast conditioned medium. Together, these studies reveal the novel findings that PAR2, a second protease-activated G protein-coupled receptor, has a critical role in breast cancer cell migration and invasion and functions as the endogenous receptor for coagulant proteases VIIa and Xa in these cells (1).

ii) Carcinoma of the prostate (CaP):

- the inhibition of MMP-2 and MMP-9 in DU145 cells by EGCG is mediated via inhibition of phosphorylation of ERK1/2 and p38 pathways, and inhibition of activation of transcription factors c-jun and NF-kappaB. EGCG may play a role in prevention of invasive metastatic processes of both androgen-dependent and -independent prostate carcinoma.
Practical hint: Since fibroblast conditioned medium (FCM) partially mimics in vivo tumor-host microenvironment, DU145 cells were co-cultured in FCM.

References:

1 Morris DR etal Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells Cancer Res. 2006 Jan 1;66(1):307-14

2 Vayalil PK etal Treatment of epigallocatechin-3-gallate inhibits matrix metalloproteinases-2 and -9 via inhibition of activation of mitogen-activated protein kinases, c-jun and NF-kappaB in human prostate carcinoma DU-145 cells Prostate. 2004 Apr 1;59(1):33-42.

Survey Part- A ] Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment

b) TGF-Beta: Serine/threonine protein kinases: TKL group(TGFBR2 family - Transforming growth factor, beta receptor II) and associated proteins:


Transforming growth factor-beta (TGF-beta) plays complex dual roles as an inhibitor and promoter of tumor progression. Although the influence of the stromal microenvironment on tumor progression is well recognized, little is known about the functions of TGF-beta signaling in the stroma during tumor progression. In a co-xenograft model, the authors have demonstrated that TGF-bR2(FspKO) fibroblasts enhance mammary carcinoma growth and metastasis in mice while increasing hepatocyte growth factor (HGF) expression and c-Met signaling downstream pathways including signal transducers and activators of transcription 3 (Stat3) and p42/44 mitogen-activated protein kinase (MAPK). The results show that TGF-beta signaling in fibroblasts suppresses tumor metastasis by antagonizing HGF/c-Met signaling within tumor epithelial cells. Furthermore, this co-xenograft model represents a unique context to study stromal TGF-beta and HGF signaling in mammary tumorigenesis(1).

Independent studies:
In Crouzon's syndrome: demonstrated about the in vitro differences between normal and Crouzon fibroblasts may be due to an imbalance in TGF beta and bFGF levels which alters the microenvironment where morphogenesis takes place. Further studies also proved that a TM domain (transmembrane domains of receptor tyrosine kinases (RTKs)) pathogenic mutation is the Ala391-->Glu mutation in fibroblast growth factor receptor 3 (FGFR3), linked to Crouzon syndrome with acanthosis nigricans, as well as to bladder cancer(2, 3)

In idiopathic pulmonary fibrosis (IPF): is characterized by fibroblast expansion and extracellular matrix accumulation. Some secreted matrix metalloproteinases (MMPs) as MMP2 are highly upregulated in IPF lungs(4), also a most common lung disease predisposing lung cancer (5) where also showed the cross-talk of epithelial abnormalities and the involvement of up-regulated p63-jag1 pathway (5).

In lung fibroblasts, TGF-beta1 induced a strong upregulation of MT3-MMP, both at the gene and protein level. This effect was blocked by genistein, a protein tyrosin kinase inhibitor and partially repressed by SB203580 a p38 MAP kinase inhibitor. Interestingly MT3-MMP (Type 3 transmembrane) that was found in fibroblastic foci was upregulated in vitro by TGF-beta1 a potent profibrotic mediator(4)

In skin tumor: Keloids are abnormal fibrous growths of the dermis that develop only in response to wounding and represent a form of benign skin tumor. Previous studies have shown increased protein levels of TGF-beta in keloid tissue, suggesting a strong association with keloid formation. Further immunoblotting analysis demonstrated that p38 MAPK was phosphorylated within 15 min and was maintained at a high level in keloid human fibroblasts (KFs) but not in normal human fibroblasts (NFs). The transcription factors activating transcription factor-2 and Elk-1 are activated by p38 MAPK, and also showed rapid and prolonged phosphorylation kinetics in KFs but not in NFs. In conclusion, increased TGF-beta2 transcription in response to serum stimulation in KFs appears to be mediated by the p38 MAPK pathway. This suggests the mechanism of keloid pathogenesis may be due in part to an inherent difference in how the fibroblasts respond to wounding(6)

Epidermal growth factor (EGF) Vs Gangliosides:
Gangliosides are shed by tumor cells and can bind to normal cells in the tumor microenvironment and affect their function. Exposure of fibroblasts to exogenous gangliosides increases epidermal growth factor (EGF)-induced fibroblast proliferation and enhances EGF receptor (EGFR)-mediated activation of the mitogen-activated protein kinase signaling pathway (Li, R., Liu, Y., and Ladisch, S. (2001) J. Biol. Chem. 276, 42782-42792).

The authors concluded that membrane ganglioside enrichment of normal fibroblasts (such as by tumor cell ganglioside shedding) facilitates receptor-receptor interactions (possibly by altering membrane topology), causing ligand-independent EGFR dimerization and, in turn, enhanced EGF signaling(7).

References:

1Cheng N etal Enhanced hepatocyte growth factor signaling by type II transforming growth factor-beta receptor knockout fibroblasts promotes mammary tumorigenesis Cancer Res. 2007 May 15;67(10):4869-77

2Baroni T etal Crouzon's syndrome: differential in vitro secretion of bFGF, TGFbeta I isoforms and extracellular matrix macromolecules in patients with FGFR2 gene mutation Cytokine. 2002 Jul 21;19(2):94-101.

3 Li E etal FGFR3 dimer stabilization due to a single amino acid pathogenic mutation J Mol Biol. 2006 Feb 24;356(3):600-12

4García-Alvarez J etal Membrane type-matrix metalloproteinases in idiopathic pulmonary fibrosis Sarcoidosis Vasc Diffuse Lung Dis. 2006 Mar;23(1):13-21

5 Murata K etal p63 - Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis Exp Mol Pathol. 2007 Apr 10;

6 Xia W etal P38 MAP kinase mediates transforming growth factor-beta2 transcription in human keloid fibroblasts Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R501-8.

7 Liu Y etal Exogenous ganglioside GD1a enhances epidermal growth factor receptor binding and dimerization J Biol Chem. 2004 Aug 27;279(35):36481-9.

Abstracts for basic references/facts:

i) Alvarez RJ etal Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines Kidney Int. 1992 Jan;41(1):14-23

Fibroblasts in parenchymal organs potentially contribute extracellular matrix to local fibrogenic processes. This contribution, in some circumstances, may be initiated by cytokines disseminated from inflammatory lesions. Different populations of fibroblasts, however, might respond distinctively to this cytokine bath depending on the microenvironment in which they reside. We have begun to explore this issue using syngeneic, low-passage fibroblasts cultured in serum-free media that were derived originally from the dermis (DFBs) and from tubulointerstitium (TFBs) of the kidney. Our findings indicate that, while fibroblasts from each compartment appear similar at the ultrastructural level, there are a variety of functional differences which distinguish their proliferative response, and their collagen secretory response (types I, III, IV, and V) following challenge with various doses of immune-relevant cytokines (TGF beta, EGF, IL-1, IL-2 and gamma IFN) in culture. DFBs, for example, express more surface EGF receptors than do TFBs, and, as a consequence, exhibit a more robust proliferative response to EGF in serum-free media. Unstimulated DFBs also secrete more collagen types I and III than TFBs, while unstimulated TFBs secrete more types IV and V. The expression of these collagens in TFBs was confirmed by Northern blot hybridization. When these sets of fibroblasts were further stimulated by cytokines, some of the cytokines not only differentially effect the secretion of various species of collagens within the same group of cells, but also between cells from populations which are anatomically distinct. DFBs, furthermore, at mid-level doses of cytokine, demonstrated a general trend towards less secretion of all types of collagen (particularly for TGF beta, EGF, and IL-2), while TFBs seemed less repressive. In TFBs the cytokine-induced responses for collagen types I and III tended to be discordant, and for types I and IV EGF inhibited, while TGF beta stimulated the secretory process. These findings speak collectively for the presence of a functional heterogeneity among organ-based populations of syngeneic fibroblasts in normal tissues.

ii) Chesi M etal Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma Blood. 2001 Feb 1;97(3):729-36.


The t(4;14) translocation occurs frequently in multiple myeloma (MM) and results in the simultaneous dysregulated expression of 2 potential oncogenes, FGFR3 (fibroblast growth factor receptor 3) from der(14) and multiple myeloma SET domain protein/Wolf-Hirschhorn syndrome candidate gene 1 from der(4). It is now shown that myeloma cells carrying a t(4;14) translocation express a functional FGFR3 that in some cases is constitutively activated by the same mutations that cause thanatophoric dysplasia. As with activating mutations of K-ras and N-ras, which are reported in approximately 40% of patients with MM, activating mutations of FGFR3 occur during tumor progression. However, the constitutive activation of ras and FGFR3 does not occur in the same myeloma cells. Thus the activated forms of these proteins appear to share an overlapping role in tumor progression, suggesting that they also share the signaling cascade. Consistent with this prediction, it is shown that activated FGFR3-when expressed at levels similar to those seen in t(4;14) myeloma-is an oncogene that acts through the MAP kinase pathway to transform NIH 3T3 cells, which can then generate tumors in nude mice. Thus, FGFR3, when overexpressed in MM, may be not only oncogenic when stimulated by FGF ligands in the bone marrow microenvironment, but is also a target for activating mutations that enable FGFR3 to play a ras-like role in tumor progression.

iii) Kerry A Brenner Regulation of fibronectin matrix assembly by activated Ras in transformed cells Oncogene (2000) 19, 3156-3163

Fibronectin extracellular matrix plays a critical role in the microenvironment of cells. Loss of this matrix frequently accompanies oncogenic transformation, allowing changes in cell growth, morphology, and tissue organization. The HT1080 human fibrosarcoma cell line is deficient in formation of fibronectin matrix fibrils but assembly can be induced by the glucocorticoid dexamethasone. Here we show that fibronectin assembly can also be restored by stimulation of alpha5beta1 integrin with activating antibody or with Mn2+ suggesting that integrin activity is reduced in these cells. While dexamethasone promoted actin stress fiber formation, actin filaments remained cortical following Mn2+ treatment showing that the dexamethasone effect is not due solely to cytoskeletal changes. HT1080 cells have one activated allele of N-ras and PD98059 inhibition of signaling from Ras through ERK increased fibronectin matrix accumulation. Conversely, the p38 MAP kinase inhibitor SB203580 blocked induction of matrix and increased ERK phosphorylation. Thus, two MAP kinase pathways contribute to the control of integrin-mediated fibronectin assembly. ERK activity and fibronectin assembly were linked in three different ras-transformed cell lines but not in SV40- or RSV-transformed cells indicating that oncogenic Ras uses a distinct mechanism to down-regulate cell-fibronectin interactions.

Survey Part- A ] Serine/Threonine and Tyrosine Protein Kinases in "Fibroblast" of Stroma (cancer) Microenvironment

survey results:

a)

Tyrosine protein kinases (PDGFR family: - PDGF( Platelet-derived growth factor) and associated proteins:

->Seems like PDGF and families kinases are well studied in this stroma-cancer- microenvironment while comparing to the other kinase proteins<-:

Local production of Platelet-derived growth factor (PDGF) in the marrow microenvironment stimulates tumor growth and progression by affecting tumor and stromal cells as well as may play an important role in regulating hematopoietic and stromal cell proliferation(1,5)

The potential mechanisms underlying this tumorigenic conversion is that, in in-vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation by paracrine (1) stimulation and autocrine growth(2) of the stroma, (and increased expression of the hepatocyte growth factor ) but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation and benign tumor formation phenotype(1).

In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation.

This PDGF has also been shown to physically interact with glycosaminoglycans which are abundant in the fibrosarcoma cell microenvironment. In this study, the authors found that chondroitin sulfate A enhance the mitogenic activity of platelet-derived growth factor in fibrosarcoma cells utilizing a pathway which involves tyrosine kinases. This result introduces a new modulating role for chondroitin sulfate in signalling pathways critical for cancer growth(2).

Platelet-derived growth factor (PDGF) also plays role in stimulating multipotent and erythroid progenitors as well as stromal fibroblasts. Any of the three dimeric forms of PDGF (AA, AB, or BB) could potentially interact with these cells (5). Endothelial cells and fibroblasts are important constituents of the haemopoietic microenvironment. Growth and function of these cells are controlled by a variety of cytokines, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Immunofluorescence studies and time course analyses suggested that the primary effect of the inhibitors was interference with the proliferation and function of fibroblasts and endothelial cells which in turn resulted in decreased haemopoiesis and increased adipogenesis. This was associated with decreased levels in conditioned media of granulocyte-macrophage colony-stimulating factor, interleukin-6 and leptin. VEGF and PDGF may play a hitherto underestimated role in the control of blood cell formation. VEGF/PDGF receptor inhibitors may have therapeutic potential in stroma diseases such as myelofibrosis. Since they weaken the stimulatory signals provided by the microenvironment, they may also be of value in the treatment of leukaemia and other neoplastic bone marrow diseases(3).

In an another study(4), stimulation of Swiss 3T3 fibroblasts with platelet-derived growth factor (PDGF) results in a transient increase in intracellular free Ca2+ concentration ([Ca2+]i) and a phospholipase A2 (PLA2)-dependent release of arachidonic acid (AA). This PDGF-induced PLA2 dependent AA release in Swiss 3T3 fibroblast is regulated by both PKC-dependent and -independent mechanisms, and is activated by high concentrations of free Ca2+ in the microenvironment beneath the plasma membrane during Ca2+ influx via plasma-membrane Ca2+ channels, despite buffering by EGTA of [Ca2+]i in the bulk cytoplasm of the cell( 4).

[One curiosity question is: does PDGF play any role in the osteoblastic niche???]

Further more, studies in medium conditioned by MBA-2, murine bone marrow-derived endothelial cells, contains PDGF activity that competes for PDGF binding to human foreskin fibroblasts and is mitogenic for these fibroblasts(5). In addition to this, further studies were also found that cytokines such as transforming growth factor-beta (TGF-beta) regulate hematopoiesis and stimulate PDGF in certain mesenchymal cells (5).

Referencess:

1 Lederle W etal in Am J Pathol 2006 Nov;169(5):1767-83 Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells

2Fthenou E etal in Int J Biochem Cell Biol. 2006;38(12):2141-50 Chondroitin sulfate A chains enhance platelet derived growth factor-mediated signalling in fibrosarcoma cells.
3 Dührsen U etal in Growth Factors 2001;19(1):1-17. Effects of vascular endothelial and platelet-derived growth factor receptor inhibitors on long-term cultures from normal human bone marrow.
4. Chow SC etal in Biochim Biophys Acta. 1993 Oct 7;1179(1):81-8Mechanisms of platelet-derived growth factor-induced arachidonic acid release in Swiss 3T3 fibroblasts: the role of a localized increase in free Ca2+ concentration beneath the plasma membrane and the activation of protein kinase C.
5. Abboud SL. Blood. 1993 May 15;81(10):2547-53 A bone marrow stromal cell line is a source and target for platelet-derived growth factor

Serine/Threonine Protein Kinases and Tyrosine Protein Kinases in stroma- cancer microenvironment, with some (basic) reference pictures

Microecology of the tumour–host invasion field (picture above):
(Invasive carcinoma is viewed as a pathology of multiple cell societies inhabiting the epithelial/mesenchymal stromal unit. Transition to invasive carcinoma is preceded by the activation of host fibroblasts, immune cells and endothelial cells. Invasion occurs in a localized zone of cross-talk and cooperation between the stromal cells and the premalignant epithelium (depicted as zones demarked by dashed lines). Cytokine and enzyme exchange between the participating cells stimulates migration of both cell types towards each other and modifies the adjacent extracellular matrix/basement membrane. The result is a breakdown of normal tissue boundaries)









Molecular cross-talk at the invasion front (picture above):
(Example mediators are shown. Motility and invasion is a bi-directional process. Fibroblasts produce chemoattractants such as SF/HGF, which stimulates motility of tumour cells by binding to the Met receptor (c-Met). Tumour cells produce angiogenesis factors such as VEGF and bFGF, which bind to receptors on stromal vascular cells and cause increased vascular permeability, endothelial proliferation, migration and invasion. Fibroblasts and endothelial stromal cells elaborate latent enzymes, including MMPs and uPA, which dock on the surface of the carcinoma invadopodia and become activated, thereby degrading the ECM, and clearing a pathway. ECM degradation releases bound growth factors such as TGF- and EGF, which bind to cognate receptors (TGF- R and uPAR) on the carcinoma cell. ECM proteolysis also exposes cryptic RGD sites, which are recognized by integrins. Cross-talk between signal pathways within the carcinoma cells links motility, proliferation and pro-survival signals. For example, phosphorylation of FAK through Met and integrin signalling transduces signals through Ras, PI(3)K, -catenin and MLCK, causing cytoskeletal remodelling, ERK activation of mitogenesis, and sustainment of survival through phosphorylation of Akt)

Reference:
Lance A. Liotta etal Progress: The microenvironment of the tumour–host interface Nature 411, 375-379 (17 May 2001)








Epithelia can be reactive to a changing stromal environment (picture above):
(a, Homeostatic interactions between the epithelia and fibroblasts are maintained by positive and negative signals that influence the proliferation and differentiation of both the stroma and epithelia. b, When signalling by a suppressive growth factor (TGF- ) to the stromal fibroblasts is lost (red starburst), it leads to elevated fibroblast proliferation. Resulting paracrine factors (for example, HGF) and potential modifications in the ECM can stimulate the proliferation and transformation of epithelial cells in vivo in some tissues)







Regulation of epithelial growth, differentiation and apoptosis (table)

Reference:

Neil A. Bhowmick etal Stromal fibroblasts in cancer initiation and progression Nature 432, 332-337 (18 November 2004)





While studying the stromal cancer (stem) microenvironment, one area are really fascinating me lot especially their high level of involvement towards identify novel therapeutic targets followed by develop therapeutics, find solutions for various cancers associated problems as well as helping to study the basic of stem-cell biology, etc etc. Such one field is also known as Serine/Threonine Protein Kinases and Tyrosine Protein Kinases.

The surprise thing is that though there are more than 70 numbers of Kinase families playing role within the human system, but just few of them only have been studied (ing), on the field of stroma- cancer cells microenvironment.

Having interest to gain some knowledge on the role of this cross-talk, complex system within the stromal – cancer –microenvironment I would like to begin from the cell fibroblasts (as one of the components of stroma cancer microenvironment ) and its association with kinases.

Since new to this field I would also likes to add the basic, key informative abstracts for further (quickest) reference purpose.


Cross-talk or associated role of fibroblast with stroma components

:- >(pictures above)<-:

stroma cancer microenvironment -basics

An increasing body of research indicates that stroma surrounding cancer cells plays an important role in the development and subsequent behavior of the tumor. Studies using a wide range of techniques, including stromal cell isolation, modification of stromal-specific gene expression, and recreation of specific microenvironment conditions in culture, have demonstrated that stroma can promote cancer and that the expression patterns within the stroma can influence clinical outcome. Major hurdles in the study of the cancer stroma revolve around the cellular complexity of the tumor microenvironment,
both in modeling the microenvironment and discovering/isolating pure populations of stromal cell types.

An alternative, emerging, avenue of therapy focuses on targeting various non-neoplastic cells that are associated with the tumor microenvironment, such as endothelial cells. Since stromal cells within the tumor are thought to be ‘normal’ and less genetically labile than the neoplastic cells, development of acquired resistance to therapy may be less likely. As such, the tumor stroma may be an excellent target for directed therapy.

CELLS OF THE STROMA:
The stroma consists of a compilation of cells, including fibroblasts/myofibroblasts, glial, epithelial, fat, immune, vascular, smooth muscle, and immune cells along with the extra cellular matrix (ECM) and extra cellular molecules. Among this, the most widely studied to date are the fibroblasts, immune cells, and the vascular cells. Rrecently, research groups are also trying to identify new subtypes of fibroblasts and their role in cancer, develop markers, etc by using the studies of profiles from two different STTs (soft tissue tumors (STTs), desmoid-type fibromatosis (DTF) and solitary fibrous tumor (SFT).


References:

1 Li H etal Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem. 2007 Jul 1;101(4):805-15.

2) Robert B West etal Experimental approaches to the study of cancer–stroma interactions: recent findings suggest a pivotal role for stroma in carcinogenesis Laboratory Investigation (2007), 1–4