Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A small population of stem cell-like precursors in solid tumors are linked to histological composition, progression, angiogenesis, metastasis, recurrence and drug resistance of a variety of malignant tumors. Oligoastrocytoma is the most common brain mixed glioma composed of mixed cells of oligodendroglial and astrocytic phenotypes. Identification and characterization of stem cell-like precursors in oligoastrocytoma may shed light on the oncogenesis of this unique type of tumor and assist in the design of novel therapeutic strategy. Here, tumor stem cell-like precursors were identified from primary human anaplastic oligoastrocytomas by labeling of the tumor sections with nestin and CD133. Tumor cells were cultured in vitro in stem cell medium with growth factors and the capacity of the surviving stem cell-like precursors to form tumor spheres was tested. The tumor spheres were further injected subcutaneously into nude mice to observe the contribution of stem cell-like precursors to histological composition and tumor progression. We found that primary human oligoastrocytoma tissues contained nestin+/CD133+ stem cell-like precursors. These cells differentiated into tumor cells with both oligodendroglial and astrocytic characteristics and formed tumor spheres in vitro, which upon implantation in nude mice, grew into tumor nodules containing nestin+/CD133+ cells at levels higher than in the primary tumor tissues. This study revealed for the first time that anaplastic human oligoastrocytomas contained stem cell-like precursors, which exhibit neural stem cell properties with tumorigenicity. These stem cell-like precursors may be responsible for the oligodendroglial and astrocytic components of human oligoastrocytoma and should be considered as therapeutic targets.
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PMID:Isolation and characterization of stem cell-like precursor cells from primary human anaplastic oligoastrocytoma. 1766 Aug 1

B7-H4, a newly discovered member of B7 family that negatively regulates T cell-mediated immunity, may facilitate tumor progression by undermining host immunity. Recent studies show that brain tumor stem-like cells (TSCs) contribute to tumorigenesis. However, the relationship between B7-H4 and the clinical behavior of brain TSCs remains unclear. In this study, we found that B7-H4 was expressed in cultured tumor cells from human gliomas (n = 5) and medulloblastomas (n = 3). Double immunostaining indicated that B7-H4 was primarily restricted to non-dividing (Ki67(-)) cultured tumor cells. Tumor cells cultured under medium conditions favoring the growth of neural stem cells were able to form primary and secondary spheres, along with expression of neural stem/progenitor cell markers. These cells differentiated into different neural lineages when cultured in differentiation medium, indicating that these cells have TSCs characteristics. Double immunostaining showed that TSCs consisted of proliferative (Ki67(+)) and quiescent (Ki67(-)) cells. We also found that B7-H4 was expressed in a small population of CD133(+) cells sorted by flow cytometry. Interestingly, both CD133(+) and CD133(-) cells were tumorigenic in SCID mice in vivo. However, CD133(+) cells-initiated glioblastomas showed a higher proliferation index, compared to CD133(-) cells-induced glioblastomas in vivo. Secondary glioma cells derived from CD133(+) or CD133(-) cell xenografts expressed B7-H4 as well. Our data suggest B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subpopulation of brain TSCs, and CD133(-) tumor cells also have the capacity to initiate brain formation in vivo.
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PMID:B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. 1847 83

This review presents compelling evidence that human glioblastoma is a heterogenous tumor composed from tumor cells and small portion of cancer stem cells -- tumor-initiating cells, which have a high tumorigenic potential and a low proliferation rate. Glioma cancer stem cells are phenotypically similar to the normal stem cells, they express CD133 gene and other genes characteristic of neural stem cells and posses the self-renewal potential. Cancer stem cells derived from glioblastoma are capable recapitulate original polyclonal tumors when xenografted to nude mice. They are chemoresistant and radioresistant and therefore responsible for tumor progression and recurrence after conventional glioblastoma therapy. Cancer stem cells contribute to glioma radioresistance by an increase of DNA repair capacity through preferential activation of the DNA damage response checkpoints. Potential therapies that modulate or target cancer stem cells are also reviewed. Mesenchymal stem cells and/or neural stem cells were shown to target brain tumors therefore these cells are considered as an effective delivery system to target and disseminate therapeutic agents to brain tumors. Stem cell-based gene therapies for glioblastoma were shown in experiments to be effective way to target brain tumors. Effects of bone morphogenetic protein (BMP4) on glioma cancer stem cells are also reviewed. BMP4 reduces effectively proliferation of CD133 positive cells in vitro and the tumor growth in vivo. BMP4 may act as a key inhibitory regulator of cancer initiation and therefore may be used in combined stem cell-based therapy as a non-cytotoxic therapeutic agent.
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PMID:Glioblastoma and stem cells. 1866 45

The biology of the normal colonic mucosa suggests that colon cancer originates from normal colon stem cells. CD44 cancer stem cells have been identified in breast and prostate cancer, and we therefore examined whether CD44 similarly identified colon cancer stem cells. Initial assays found CD44(hi) colon tumor cells to have enhanced soft agar colony-forming ability. Subsequently, CD44(hi) cells isolated from 4 primary colon adenocarcinoma xenografts were found to be highly tumorigenic in immune deficient mice. CD44(hi) cells consistently formed tumors with 1,000 cells, and in multiple experiments, as few as 10 and 100 CD44(hi) cells formed tumors in 7/10 and 21/28 mice, respectively. In contrast, CD44(-) colon tumor cells were either nontumorigenic or 10-50-fold less tumorigenic. CD44(hi) cells could be serially passaged up to 4 times in vivo, suggesting self-renewal capacity, and formed tumors that recapitulated the heterogeneity of the original patient tumor. CD44(hi) cells were significantly enriched for nuclear activated beta-catenin, a key element in normal stem/progenitor cells and in early colon tumor progression. Bromodeoxyuridine (BrdU) labeling studies indicated that CD44(hi) cells divide slowly relative to the CD44(-) cells, suggesting their tumorigenicity is not simply due to faster proliferation. Aldehyde dehydrogenase (ALDH) sort further increased the tumorigenicity of CD44(hi) cells from 2/2 patient tumors, but CD133 tumor cells in our hands did not have increased tumorigenicity. Our observations indicate that CD44 is a marker of stem-like cells in colon cancer, and support the use of additional markers to further purify colon cancer stem cells.
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PMID:Characterization of a subpopulation of colon cancer cells with stem cell-like properties. 1907 81

Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1(+) cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1(+) cells increased in number and became distributed farther up the crypt. CD133(+) and CD44(+) cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic-severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor(-) cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44(+) or CD133(+) serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.
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PMID:Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. 1933 70

A common feature in the progression of multiple human malignancies is the protracted deregulation of the coagulation system, often referred to as cancer coagulopathy. Indeed, cancer cells and their vascular stroma often exhibit procoagulant properties, of which deregulation of tissue factor (TF) expression is a notable, although not the sole example. These changes can be traced to oncogenic influences affecting epidermal growth factor receptor (EGFR), EGFRvIII, K-ras, p53, PTEN, and probably many other proto-oncogenes and tumor suppressors in tumor parenchyma. Cancer stem cells (CSCs)/tumor initiating cells (TICs) are thought to represent the primary target and the main cellular effector through which oncogenic mutations exert their tumor-inducing effects. In so doing, CSCs/TICs depend on interactions with the tumor vasculature, which forms supportive niches for their clonal growth. We postulate that TF contributes to these interactions (directly or indirectly) through procoagulant and signaling effects, the latter executed in concert with juxtaposed protease activated receptors (mainly PAR-1 and PAR-2). TF/PAR system acts as a "blood sensing" mechanism, whereby cancer cells, including CSCs/TICs, may respond to plasma proteases (Factors VIIa, Xa, and IIa) and their related microenvironmental changes (fibrin deposition, activation of platelets). A growing body of still largely circumstantial evidence suggests that these events may contribute to the CSC/TIC niche, which could influence tumor initiation, metastasis, recurrence, and therapeutic intractability. Indeed, certain types of cancer cells harboring markers of CSCs (CD133) exhibit elevated TF expression and depend on this receptor to efficiently initiate tumor growth. We propose that both tumor cell-associated and host-related TF could influence the properties of CSCs, and that agents targeting the TF/PAR system may represent a hitherto unappreciated therapeutic opportunity to control cancer progression by influencing the CSC/TIC compartment.
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PMID:Tissue factor and cancer stem cells: is there a linkage? 1962 88

The insulin-like growth factor (IGF) system is involved in cell migration, which plays an important role in cancer progression. It has been shown that cancer progression correlates with the level of circulating human hematopoietic stem and progenitor cells (HSPCs) expressing CD34 and/or CD133. However, it is unknown whether factors released from cancer cells, including soluble compounds of the IGF system, recruit these HSPCs via enhancing their migration. Our study showed the expression of type I IGF receptor (IGF-IR) in human HSPCs expressing CD34 and/or CD133. In an indirect co-culture model, soluble factors released from human lung epithelial cancer cells (H358, H322) increased the migration of CD34-/CD133+ cells towards cancer cells, whereas migration of CD34+/CD133+ or CD34+/CD133- cells remained unchanged. The lung epithelial cancer cell lines H358 and H322, exhibited a high expression of IGFBP-2, -4 and -6 but not IGF-I and IGFBP-3. Subsequent analyses with those soluble compounds of the IGF system revealed a dose-dependent stimulating effect of the IGFBP-2 and -4 on the migration of CD34-/CD133+ cells. In contrast, IGF-I and IGFBP-3 and -6 did not influence the migration of CD34-/CD133+ cells. Because IGFBPs are involved in cell migration via IGF-dependent and -independent mechanisms, our study indicates that IGFBP-2 and -4, which are expressed in lung epithelial cancer cells, enhance the migration of CD34-/CD133+ HSPCs independent of IGF-I.
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PMID:Insulin-like growth factor binding proteins-2 and -4 enhance the migration of human CD34-/CD133+ hematopoietic stem and progenitor cells. 1995 6

Oncogenic transformation and aberrant cellular differentiation are regarded as key processes leading to malignancy. They produce heterogenous cellular populations including subsets of tumour initiating cells (TICs), also known as cancer stem cells (CSCs). Intracellular events involved in these changes profoundly impact the extracellular and systemic constituents of cancer progression, including those dependent on the vascular system. This includes angiogenesis, vasculogenesis, activation of the coagulation system and formation of CSC-related and premetastatic niches. Tissue factor (TF) is a unique cell-associated receptor for coagulation factor VIIa, initiator of blood coagulation, and mediator of cellular signalling, all of which influence vascular homeostasis. Our studies established a link between oncogenic events, angiogenesis and the elevated expression of TF in several types of cancer cells. The latter suggests that cancer coagulopathy and cellular events attributed to the coagulation system may have cancer-specific and genetic causes. Indeed, in human glioma cells, a transforming mutant of the epidermal growth factor receptor (EGFRvIII) triggers not only the expression of TF, but also of its ligand (factor VII) and protease activated receptors (PAR-1 and PAR-2). Consequently, tumour cells expressing EGFRvIII become hypersensitive to contact with blood borne proteases (VIIa, thrombin), which upregulate their production of angiogenic factors (VEGF and IL-8), and contribute to formation of the growth promoting microenvironment (niche). Moreover, TF overexpression accompanies features of cellular aggressiveness such as markers of CSCs (CD133), epithelial-to-mesenchymal transition (EMT) and expression of the angiogenic and prometastatic phenotype. Conversely, TF blocking antibodies inhibit tumour growth, angiogenesis, and especially tumour initiation upon injection of threshold numbers of tumourigenic cells. Likewise, TF depletion in the host compartment (e.g. in low-TF mice) perturbs tumour initiation. These observations suggest that both cancer cells and their adjacent host stroma contribute TF activity to the tumour microenvironment. We postulate that the TF pathway may play an important role in formation of the vascular niche for tumour initiating CSCs, through its procoagulant and signalling effects. Therapeutic blockade of these mechanisms could hamper tumour initiation processes, which are dependent on CSCs and participate in tumour onset, recurrence, drug resistance and metastasis.
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PMID:Role of the tissue factor pathway in the biology of tumor initiating cells. 2043 4

Tumors that display a highly metastatic phenotype contain subpopulations of cells that display characteristics similar to embryonic stem cells. These cells exhibit the ability to undergo self-renewal; slowly replicate to retain a nucleoside analog label, leading to their definition as "label-retaining cells"; express specific surface markers such as CD44(+)/CD24(-/low) and CD133; and can give rise to cells of different lineages (i.e., they exhibit multipotency). Based on these characteristics, as well as their demonstrated ability to give rise to tumors in vivo, these cells have been defined as tumor-initiating cells (TICs), tumor-propagating cells, or cancer stem cells (CSCs). These cells are highly resistant to chemotherapeutic agents and radiation and are believed to be responsible for the development of both primary tumors and metastatic lesions at sites distant from the primary tumor. Established cancer cell lines contain CSCs, which can be propagated in vitro using defined conditions, to form 3D tumor spheroids. Because the vast majority of studies to identify cancer-associated genes and therapeutic targets use adherent cells grown in 2 dimensions on a plastic substrate, the multicellular composition of these 3D tumor spheroids presents both challenges and opportunities for their imaging and characterization. The authors describe approaches to image and analyze the properties of CSCs within 3D tumor spheroids, which can serve as the basis for defining the gene and protein signatures of CSCs and to develop therapeutic strategies that will effectively target this critically important population of cells that may be responsible for tumor progression.
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PMID:Imaging and analysis of 3D tumor spheroids enriched for a cancer stem cell phenotype. 2063 4

Although CD133 has been reported to be a promising colon cancer stem cell marker, the biological functions of CD133+ colon cancer cells remain controversial. In the present study, we investigated the biological differences between CD133+ and CD133- colon cancer cells, with a particular focus on their interactions with cancer-associated fibroblasts, especially CD10+ fibroblasts. We used 19 primary colon cancer tissues, 30 primary cultures of fibroblasts derived from colon cancer tissues and 6 colon cancer cell lines. We isolated CD133+ and CD133- subpopulations from the colon cancer tissues and cultured cells. In vitro analyses revealed that the two populations showed similar biological behaviors in their proliferation and chemosensitivity. In vivo analyses revealed that CD133+ cells showed significantly greater tumor growth than CD133- cells (P=0.007). Moreover, in cocultures with primary fibroblasts derived from colon cancer tissues, CD133+ cells exhibited significantly more invasive behaviors than CD133- cells (P<0.001), especially in cocultures with CD10+ fibroblasts (P<0.0001). Further in vivo analyses revealed that CD10+ fibroblasts enhanced the tumor growth of CD133+ cells significantly more than CD10- fibroblasts (P<0.05). These data demonstrate that the in vitro invasive properties and in vivo tumor growth of CD133+ colon cancer cells are enhanced in the presence of specific cancer-associated fibroblasts, CD10+ fibroblasts, suggesting that the interactions between these specific cell populations have important roles in cancer progression. Therefore, these specific interactions may be promising targets for new colon cancer therapies.
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PMID:Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(-) cancer cells. 2071 32


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