It's really interesting here..! This week Stem Cells, there is an interesting paper! A research group has found that the proto-oncogene kinase pim-1 and pim-3 (in detail: Serine/threonine protein kinases -> CAMK group -> PIM family -> proto-oncogene serine/threonine-protein kinase Pim-1 and Pim-3) plays important role in stem-cell renewal!!
The authors have demonstrated a novel role of proto oncogene Pim 1 and 3 in ES self-renewal as well as exhibited resistance to leukemia inhibitory factor (LIF) starvation, a gp130 family cytokines proteins, which is also regulating the subsequent protein, Stat3 (Signal Transducer and Activator of Transcription 3).
Irène Aksoy etal Self-Renewal of Murine Embryonic Stem Cells Is Supported by the Serine/Threonine Kinases Pim-1 and Pim-3 Stem Cells (December 2007; Vol. 25, No. 12, pp. 2996 -3004).
The most curiosities and surprising part is that , until this time (including the previous (post)surveying on the Serine/threonine protein kinases in (stem cell niche/stromal-fibroblast cell– microenvironment) I used to think that the Serine/threonine kinase protein means it’s always only meant for aberrant expressions or for druggable targets, preferably for cancer.....! So seems like the paper are igniting an additional, the most exciting way of thinking on the field of serine/threonine kinase families proteins …!
Tuesday, November 13, 2007
Wednesday, November 7, 2007
some very useful reports, available in full-text, from the recent conferences
General view:
Disease focused:
* Workshop on Imaging: Cancer Biology and the Tumor Microenvironment
* Annual Meeting Abstracts from the Association for Molecular Pathology, Los Angeles, California , November 7-10, 2007 (nice reference for assay/method development)
** more interested?! Here is reports on a previous year's events (something like one stop resources!)
Methods series:
A Meeting Report: "New Technologies in Stem Cell Research" ***
PS:
i) i will up-date soon with some more interesting reports, which is under reprint requisition,
ii) ***please let me know if you experience any difficulties to download the complete text so that I can share the article (and the author dr. Kathleen Sakamoto is really a sporty type!)
Sunday, November 4, 2007
numbers of curiosity questions, from the previous hypothesis post (of stem-cell niche in normal and pathological conditions ...)
Though the preparations on the previous (post) mini hypothesis and giving me opportunities to read number of literatures as well as guiding me to have some depth overview on the stem-cell niche field, interestingly it’s also leaving me number of curiosity questions. such as,
I) on the part of cell-fusion:
i) In general or within the context of cancer, are there any relationships between cell-fusion and the G0/G1 cell cycle?
(thought provoking key paper:
Lizard G etal in Cell fusion of human and mouse cells as a source for new cells retaining human markers. Analysis of DNA content, membrane and cytoplasmic antigen expression. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(5):301-6
ii) After cell-fusion followed by reductive division explain about the presence of epithelial-mesenchymal transition (EMT) markers in the newly formed cells. Is this reductive division have any relationship with senescence?
(Key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12072-7. Epub 2001 Oct 2)
iii) Does the cell fusion process also occur between the 'cancer-associated fibroblast' (CAFs) and endothelial progenitor cells (which is recruited by CAFs)?
II) on the part of therapeutic targets:
i) apart from the identification of metalloproteinases in cancer-associated fibroblast (CAFs) (1) until now there is only one Tyrosine protein kinase (Platelet-Derived Growth Factor (PDGF), a PDGFR family) has been studied /correlated with the CAFs cells (2) so could this PDGF become a molecular therapeutic target of CAFs?
Key papers:
1.Rosenthal EL Expression of proteolytic enzymes in head and neck cancer-associated fibroblasts. Arch Otolaryngol Head Neck Surg. 2004 Aug;130(8):943-7)
2. Mueller L Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases Cancer Lett. 2007 Jun 8; 250(2):329-38. Epub 2006 Dec 4.).
ii) Interestingly, one of the CAFs secretary factor know as S100A4 has a binding site for TCF (t-cell receptor) as well as play role with beta-catenin. So could it also become as a therapeutic target for any metastasis cancer, by interrupting their cell-cell interactions (for examples), ...?
(key paper:
Stein U etal The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology. 2006 Nov; 131(5):1486-500. Epub 2006 Aug 22)
III) in general:
i) Once a lesion initiated, CAFs have been shown to assist in proliferation and progression of cancer through the production of growth factors, chemotactic factors, angiogenesis factors, matrix metalloproteinases MMPs towards invasion and spread of cancer cells in initiated, non tumorogenic epithelial cells. Since CAFs playing the tumorigenic role within the cancer microenvironment, its ability to form cancer, ability to attract progenitors, ability to transform epithelial cells, etc shall we call these 'cancer-associated fibroblast' (CAFs) as an “unipotent progenitor cells” or ‘fibroblast-restricted progenitor cells’?
In other words, still it’s not clear why most late-life cancers are epithelial. Since CAFs have role in senescence (1) shall we expect that the CAFs may undergo reverse phenotype (so it could able to escape from the immune system) and express its tumorogentic behaviours in those late-life cancer?
(key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging Proc Natl Acad Sci U S A. 2001 Oct 9; 98(21):12072-7. Epub 2001 Oct 2)
ii) within the stromal-cancer microenvironment, while both cancer and the CAFs cells come together, there might be possibility of excess production of the growth factor such as S100A4, SDS???, etc. does this increase level of gradients makes any effects on their behaviour (within the niche / microenvironment)?
iv) Unclear part:
its not clear if
i) there is any role of epigenetic alterations Vs CAFs, within the context of aberrant tumor microenvironment?
ii) whether the bone marrow derived (stem) cells Vs CAFs as well as cancer stem-cell Vs stromal cells share any common genetic origins?
iii) whether the cancer stem-cells also produce the CAFs?
I would be grateful if you could offer or share any of your thoughts on these questions, which would ultimately helpful for me to improve some knowledge on the field of stem-cell niche in normal and pathologic conditions . Thank you!
Have a nice day!
I) on the part of cell-fusion:
i) In general or within the context of cancer, are there any relationships between cell-fusion and the G0/G1 cell cycle?
(thought provoking key paper:
Lizard G etal in Cell fusion of human and mouse cells as a source for new cells retaining human markers. Analysis of DNA content, membrane and cytoplasmic antigen expression. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(5):301-6
ii) After cell-fusion followed by reductive division explain about the presence of epithelial-mesenchymal transition (EMT) markers in the newly formed cells. Is this reductive division have any relationship with senescence?
(Key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12072-7. Epub 2001 Oct 2)
iii) Does the cell fusion process also occur between the 'cancer-associated fibroblast' (CAFs) and endothelial progenitor cells (which is recruited by CAFs)?
II) on the part of therapeutic targets:
i) apart from the identification of metalloproteinases in cancer-associated fibroblast (CAFs) (1) until now there is only one Tyrosine protein kinase (Platelet-Derived Growth Factor (PDGF), a PDGFR family) has been studied /correlated with the CAFs cells (2) so could this PDGF become a molecular therapeutic target of CAFs?
Key papers:
1.Rosenthal EL Expression of proteolytic enzymes in head and neck cancer-associated fibroblasts. Arch Otolaryngol Head Neck Surg. 2004 Aug;130(8):943-7)
2. Mueller L Imatinib mesylate inhibits proliferation and modulates cytokine expression of human cancer-associated stromal fibroblasts from colorectal metastases Cancer Lett. 2007 Jun 8; 250(2):329-38. Epub 2006 Dec 4.).
ii) Interestingly, one of the CAFs secretary factor know as S100A4 has a binding site for TCF (t-cell receptor) as well as play role with beta-catenin. So could it also become as a therapeutic target for any metastasis cancer, by interrupting their cell-cell interactions (for examples), ...?
(key paper:
Stein U etal The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer. Gastroenterology. 2006 Nov; 131(5):1486-500. Epub 2006 Aug 22)
III) in general:
i) Once a lesion initiated, CAFs have been shown to assist in proliferation and progression of cancer through the production of growth factors, chemotactic factors, angiogenesis factors, matrix metalloproteinases MMPs towards invasion and spread of cancer cells in initiated, non tumorogenic epithelial cells. Since CAFs playing the tumorigenic role within the cancer microenvironment, its ability to form cancer, ability to attract progenitors, ability to transform epithelial cells, etc shall we call these 'cancer-associated fibroblast' (CAFs) as an “unipotent progenitor cells” or ‘fibroblast-restricted progenitor cells’?
In other words, still it’s not clear why most late-life cancers are epithelial. Since CAFs have role in senescence (1) shall we expect that the CAFs may undergo reverse phenotype (so it could able to escape from the immune system) and express its tumorogentic behaviours in those late-life cancer?
(key paper:
Krtolica A etal Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging Proc Natl Acad Sci U S A. 2001 Oct 9; 98(21):12072-7. Epub 2001 Oct 2)
ii) within the stromal-cancer microenvironment, while both cancer and the CAFs cells come together, there might be possibility of excess production of the growth factor such as S100A4, SDS???, etc. does this increase level of gradients makes any effects on their behaviour (within the niche / microenvironment)?
iv) Unclear part:
its not clear if
i) there is any role of epigenetic alterations Vs CAFs, within the context of aberrant tumor microenvironment?
ii) whether the bone marrow derived (stem) cells Vs CAFs as well as cancer stem-cell Vs stromal cells share any common genetic origins?
iii) whether the cancer stem-cells also produce the CAFs?
I would be grateful if you could offer or share any of your thoughts on these questions, which would ultimately helpful for me to improve some knowledge on the field of stem-cell niche in normal and pathologic conditions . Thank you!
Have a nice day!
Wednesday, October 31, 2007
stem-cell niche in normal and pathological conditions ...a small hypothesis, with ‘cancer –associated fibroblasts’ (CAFs) as a model
While begun and surveying the lists of kinase family proteins (which always becoming oen of hottest field for developing drugs or drug targets..) which have been studied up-to-date in fibroblasts, one of the components of cancer (stem-cell) -stromal-niche /microenvironment, very interestingly the reading atmosphere were highly helped me to notice an un-answered question i.e., the mechanisms by which stromal cells influence the process of tumorogenesis.
Having very much interests to develop knowledge on the field of stem-cell niche I would like to develop a small hypothesis as well as some curiosity questions by utilising one of a fascinating cell called “cancer-associated fibroblasts” (CAFs) as a model, because of their interdisciplinary presence on the core area of “bone marrow derived (stem/progenitor) cells- stromal microenvironment- epithelial cells- tumorigenesis..”.
Before going in to further some basics information:
Basics of (normal) fibroblasts:
Fibroblasts are the
- Primary producers of the non-cellular scaffolds— the Extra cellular matrix,
- responsible for the deposition of the fibrillar ECM—type I, type III, and type V collagen and fibronectin as well as contribute to the formation of the basement membrane by secreting type IV collagen and laminin,
- Role in wound repair: fibroblasts are responsible for orchestrating healing, and in order to do so become ‘‘activated,’’ (help of transforming growth factor-beta (TGF-b) [1] with increased proliferation and alterations in both phenotype and secretory capacity. Production of alpha-smooth muscle actin (a-SMA) allows cells to migrate into areas of damage and contract for tissue restitution. Fibroblast activation during wound repair involves a dynamic crosstalk between the fibroblast and the injured epithelium. Direct contact with infiltrating immune cells via the adhesion molecules ICAM1 and VCAM1 [2] and response to factors secreted directly from the injured mucosa including fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) [1].
Fibroblasts within tumors:
- Fibroblasts are the main cellular component of tumor stroma comprising an integral component of the tumor,
- In some cancer types, fibroblasts constitute a larger proportion of cells within the tumor than do the cancer cells. Fibroblasts within tumors have an activated phenotype, and as such resemble fibroblasts in wound healing. These cancer-associated fibroblasts (CAFs) are functionally and phenotypically distinct from normal fibroblasts that are in the same tissue but not in the tumor environment. The distinction between these and physiologically activated fibroblasts is that they are perpetually activated, neither reverting to a normal phenotype nor undergoing apoptosis and elimination [3]
- CAFs are identified within tumor stroma by their spindyloid appearance and the expression of a-SMA; characteristics shared by activated fibroblasts in wounds, also express alpha-smooth muscle actin (alpha-SMA), vimentin, S100A4 protein/fibroblast specific protein-1 (FSP1) and type I collagen [4] stromal cell-derived factor 1 (SDF-1) [5].
Hypothesis:
An increasing body of research indicates that stroma surrounding cancer cells plays an important role in the development and subsequent behaviour of the tumor. The cancers often develop resistance to these (cancer) therapies, in large part due to their genomic inherent instability. An alternative, emerging, avenue of therapy focuses on targeting various non-neoplastic cells that are associated with the tumor microenvironment, such as endothelial cells, etc. 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 my be less likely. As such, the tumor stroma may be an excellent target for directed therapy [6].
Within the stromal-microenvironment complex, the stromal cells are also associated with epithelial cell, which promote malignant progression in genetically initiated prostatic epithelial cells resulting in tumorigenesis if there is any changes occur on these stromal-epithelial interactions [7]. Once the microenvironment encounter tissue damage/injury/ UV/ionisation effects and or inflammation followed by the initiation of progression of inflammatory pathways [8], induction of extracellular matrix-remodelling proteases etc leads to the disruptions of the normal stromal-epithelial interactions towards development of ‘reactive’ fibroblast. While forming these disorganisation and the reactive state, the bone marrow – derived (stem) cell (which already proved to be plasticity as well as have relationship with cancers such as home to tumor specific ‘pre-metastatic niche’) [9, 10] become activated and starts to support the ‘activated’ stroma towards formation of the ‘cancer –associated fibroblasts’ (CAFs), which in turn start to acts in place of the normal stromal fibroblastic cells. Here, there are two facts were supporting this thought: since the bone marrow cells contribute to cancer as means of development mimicry[11] as well as during the prostate carcinogenesis the stroma undergoes progressive loss of smooth muscle with the appearance of CAFs [7]. Since ‘cancer –associated fibroblasts’ (CAFs) have the abilities to induce the epithelial-mesenchymal transition (EMT) process, the newly formed genetic modifications will leads to formation of cell fusion between the cancer –associated fibroblasts (CAFs) and the (tumor) surrounding epithelial cells.
As a sequence of this cell-fusion and the tumor initiation, the newly formed aberrant tumor microenvironment which is not only maintained by the epigenetic alteration mechanisms in stromal cells [14] but also increased ability to support cancerous growth and further initiation process [12,13]. Followed by these newly formed, favourable ‘tumor microenvironment’, the CAFs begin to attract the endothelial progenitor cells (EPCs) by secreting a powerful chemotactic molecule also known as stromal cell-derived factor-1 (SDF-1) [5] initiating further process of trafficking/homing of the cancer –initiating (stem/progenitors) cells. As a result, the CAFs ability to migrate has increasing and begins hyperproliferation, progression to fibrosis, development of neoplasia, increasing invasiveness, and eventually metastasis.
In summary, my hypothesis is that ,
-CAFs is originated from stromal cell with the strongest support of bone marrow derived (stem) cell,
-CAFs is spreading their tumorigentic traits by cell-fusion,
-CAFs may also creates a 'mini-niche' where they may keeps the tumor-inititing cells or cancer stem cell,
References:
[1] Zeisberg M etal Role of fibroblast activation in inducing interstitial fibrosis J Nephrol. 2000 Nov-Dec;13 Suppl 3:S111-20.
[2] Clayton A etal Cellular activation through the ligation of intercellular adhesion molecule-1 J Cell Sci. 1998 Feb;111 ( Pt 4):443-53
[3]. Li H etal Tumor microenvironment: the role of the tumor stroma in cancer J Cell Biochem. 2007 Jul 1;101(4):805-15
[4] Sugimoto H, Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006 Dec;5(12):1640-6. Epub 2006 Dec 5
[5] Orimo A Stromal fibroblasts in cancer: a novel tumor-promoting cell type Cell Cycle. 2006 Aug;5(15):1597-601. Epub 2006 Aug 1.
[6] West RB, etal Experimental approaches to the study of cancer-stroma interactions: recent findings suggest a pivotal role for stroma in carcinogenesis Lab Invest. 2007 Oct;87(10):967-70. Epub 2007 Aug 13
[7] Cunha GR, Role of stroma in carcinogenesis of the prostate Differentiation. 2002 Dec;70(9-10):473-85
[8] Mueller L etal Stromal Fibroblasts in Colorectal Liver Metastases Originate From Resident Fibroblasts and Generate an Inflammatory Microenvironment. Am J Pathol. 2007 Oct 4; [Epub ahead of print]
[9] Wu XZ Bone marrow-derived cells: roles in solid tumor. Minireview Neoplasma. 2007;54(1):1-6
[10] Kaplan RN VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005 Dec 8;438(7069):820-7
[11] Cogle CR Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells. 2007 Aug;25(8):1881-7. Epub 2007 May 3
[12] Olumi AF Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999 Oct 1;59(19):5002-11
[13] Orimo A, Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion Cell. 2005 May 6;121(3):335-48
[14] Rajasekhar VK Stem Cells, Cancer, and Context Dependence. Stem Cells. 2007 Oct 25; [Epub ahead of print]
Having very much interests to develop knowledge on the field of stem-cell niche I would like to develop a small hypothesis as well as some curiosity questions by utilising one of a fascinating cell called “cancer-associated fibroblasts” (CAFs) as a model, because of their interdisciplinary presence on the core area of “bone marrow derived (stem/progenitor) cells- stromal microenvironment- epithelial cells- tumorigenesis..”.
Before going in to further some basics information:
Basics of (normal) fibroblasts:
Fibroblasts are the
- Primary producers of the non-cellular scaffolds— the Extra cellular matrix,
- responsible for the deposition of the fibrillar ECM—type I, type III, and type V collagen and fibronectin as well as contribute to the formation of the basement membrane by secreting type IV collagen and laminin,
- Role in wound repair: fibroblasts are responsible for orchestrating healing, and in order to do so become ‘‘activated,’’ (help of transforming growth factor-beta (TGF-b) [1] with increased proliferation and alterations in both phenotype and secretory capacity. Production of alpha-smooth muscle actin (a-SMA) allows cells to migrate into areas of damage and contract for tissue restitution. Fibroblast activation during wound repair involves a dynamic crosstalk between the fibroblast and the injured epithelium. Direct contact with infiltrating immune cells via the adhesion molecules ICAM1 and VCAM1 [2] and response to factors secreted directly from the injured mucosa including fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF), epidermal growth factor (EGF) [1].
Fibroblasts within tumors:
- Fibroblasts are the main cellular component of tumor stroma comprising an integral component of the tumor,
- In some cancer types, fibroblasts constitute a larger proportion of cells within the tumor than do the cancer cells. Fibroblasts within tumors have an activated phenotype, and as such resemble fibroblasts in wound healing. These cancer-associated fibroblasts (CAFs) are functionally and phenotypically distinct from normal fibroblasts that are in the same tissue but not in the tumor environment. The distinction between these and physiologically activated fibroblasts is that they are perpetually activated, neither reverting to a normal phenotype nor undergoing apoptosis and elimination [3]
- CAFs are identified within tumor stroma by their spindyloid appearance and the expression of a-SMA; characteristics shared by activated fibroblasts in wounds, also express alpha-smooth muscle actin (alpha-SMA), vimentin, S100A4 protein/fibroblast specific protein-1 (FSP1) and type I collagen [4] stromal cell-derived factor 1 (SDF-1) [5].
Hypothesis:
An increasing body of research indicates that stroma surrounding cancer cells plays an important role in the development and subsequent behaviour of the tumor. The cancers often develop resistance to these (cancer) therapies, in large part due to their genomic inherent instability. An alternative, emerging, avenue of therapy focuses on targeting various non-neoplastic cells that are associated with the tumor microenvironment, such as endothelial cells, etc. 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 my be less likely. As such, the tumor stroma may be an excellent target for directed therapy [6].
Within the stromal-microenvironment complex, the stromal cells are also associated with epithelial cell, which promote malignant progression in genetically initiated prostatic epithelial cells resulting in tumorigenesis if there is any changes occur on these stromal-epithelial interactions [7]. Once the microenvironment encounter tissue damage/injury/ UV/ionisation effects and or inflammation followed by the initiation of progression of inflammatory pathways [8], induction of extracellular matrix-remodelling proteases etc leads to the disruptions of the normal stromal-epithelial interactions towards development of ‘reactive’ fibroblast. While forming these disorganisation and the reactive state, the bone marrow – derived (stem) cell (which already proved to be plasticity as well as have relationship with cancers such as home to tumor specific ‘pre-metastatic niche’) [9, 10] become activated and starts to support the ‘activated’ stroma towards formation of the ‘cancer –associated fibroblasts’ (CAFs), which in turn start to acts in place of the normal stromal fibroblastic cells. Here, there are two facts were supporting this thought: since the bone marrow cells contribute to cancer as means of development mimicry[11] as well as during the prostate carcinogenesis the stroma undergoes progressive loss of smooth muscle with the appearance of CAFs [7]. Since ‘cancer –associated fibroblasts’ (CAFs) have the abilities to induce the epithelial-mesenchymal transition (EMT) process, the newly formed genetic modifications will leads to formation of cell fusion between the cancer –associated fibroblasts (CAFs) and the (tumor) surrounding epithelial cells.
As a sequence of this cell-fusion and the tumor initiation, the newly formed aberrant tumor microenvironment which is not only maintained by the epigenetic alteration mechanisms in stromal cells [14] but also increased ability to support cancerous growth and further initiation process [12,13]. Followed by these newly formed, favourable ‘tumor microenvironment’, the CAFs begin to attract the endothelial progenitor cells (EPCs) by secreting a powerful chemotactic molecule also known as stromal cell-derived factor-1 (SDF-1) [5] initiating further process of trafficking/homing of the cancer –initiating (stem/progenitors) cells. As a result, the CAFs ability to migrate has increasing and begins hyperproliferation, progression to fibrosis, development of neoplasia, increasing invasiveness, and eventually metastasis.
In summary, my hypothesis is that ,
-CAFs is originated from stromal cell with the strongest support of bone marrow derived (stem) cell,
-CAFs is spreading their tumorigentic traits by cell-fusion,
-CAFs may also creates a 'mini-niche' where they may keeps the tumor-inititing cells or cancer stem cell,
References:
[1] Zeisberg M etal Role of fibroblast activation in inducing interstitial fibrosis J Nephrol. 2000 Nov-Dec;13 Suppl 3:S111-20.
[2] Clayton A etal Cellular activation through the ligation of intercellular adhesion molecule-1 J Cell Sci. 1998 Feb;111 ( Pt 4):443-53
[3]. Li H etal Tumor microenvironment: the role of the tumor stroma in cancer J Cell Biochem. 2007 Jul 1;101(4):805-15
[4] Sugimoto H, Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006 Dec;5(12):1640-6. Epub 2006 Dec 5
[5] Orimo A Stromal fibroblasts in cancer: a novel tumor-promoting cell type Cell Cycle. 2006 Aug;5(15):1597-601. Epub 2006 Aug 1.
[6] West RB, etal Experimental approaches to the study of cancer-stroma interactions: recent findings suggest a pivotal role for stroma in carcinogenesis Lab Invest. 2007 Oct;87(10):967-70. Epub 2007 Aug 13
[7] Cunha GR, Role of stroma in carcinogenesis of the prostate Differentiation. 2002 Dec;70(9-10):473-85
[8] Mueller L etal Stromal Fibroblasts in Colorectal Liver Metastases Originate From Resident Fibroblasts and Generate an Inflammatory Microenvironment. Am J Pathol. 2007 Oct 4; [Epub ahead of print]
[9] Wu XZ Bone marrow-derived cells: roles in solid tumor. Minireview Neoplasma. 2007;54(1):1-6
[10] Kaplan RN VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005 Dec 8;438(7069):820-7
[11] Cogle CR Bone marrow contributes to epithelial cancers in mice and humans as developmental mimicry. Stem Cells. 2007 Aug;25(8):1881-7. Epub 2007 May 3
[12] Olumi AF Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999 Oct 1;59(19):5002-11
[13] Orimo A, Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion Cell. 2005 May 6;121(3):335-48
[14] Rajasekhar VK Stem Cells, Cancer, and Context Dependence. Stem Cells. 2007 Oct 25; [Epub ahead of print]
Tuesday, October 16, 2007
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---<-
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.
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.
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.
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