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]
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