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The role of VEGF autocrine signaling...

Das, Bikul.

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The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis./
作者:	Das, Bikul.
面頁冊數:	290 p.
附註:	Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2971.
Contained By:	Dissertation Abstracts International68-05B.
標題:	Health Sciences, Oncology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR27719
ISBN:	9780494277195

The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis.
Das, Bikul.

The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis. - 290 p.

Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2971.

Thesis (Ph.D.)--University of Toronto (Canada), 2007.

Tumor hypoxia enhances Vascular endothelial growth factor (VEGF) autocrine/paracrine signaling leading to angiogenic switch, but the role of VEGF in the self-renewal/survival of highly tumorigenic side-population (SP) cells has not been studied. Here I isolated and characterized highly migratory, and tumorigenic fraction of SP cells (SPm(hox)) in several solid tumor cell lines including neuroblastoma, rhabdomyosarcoma, medulloblastoma, and small cell lung carcinoma cell lines and evaluated the role of VEGF in the self-renewal/survival of SPm(hox) during hypoxia in neuroblastoma (SK-N-BE(2)), and rhabdomyosarcoma (RH4) cell lines. Exposure to hypoxia increased the SP fraction by 6-10 fold and SPm(hox) fraction by 2-3 fold in all the cell lines. SPm(hox) cells show very high SDF-1alpha/CXCR4 activity and could be isolated using a modified Boyden Chamber system, migrating in response to a hypoxia/hydrogen peroxide treated bone marrow stromal cell, "injured conditioned medium". In nude mice, significantly fewer (1-5x10 3) SPm(hox) cells form highly angiogenic and rapidly growing subcutaneous tumors and liver metastasis as compared to the original cell line (&sim;5x106). In an in vivo matrigel "stemness" assay, SPm(hox) cells initiate a hypoxic/oxidative-stress condition of repair/regeneration to maintain and enhance the SP-state (stemness). siRNA knockdown of Flt1 reduced the hypoxia-driven SPm(hox) self-renewal by three fold (p=0.03556) and reduced the in vivo homing of SPm(hox) to the "injured bone marrow" by 75% (p=0.0293). In addition, siRNA Flt1 knockdown reduced the hypoxia-induced Oct-4 expressing SPm (hox) cells by five fold (p = 0.0017) suggesting that VEGF/Flt1 signaling may enhance the "stemness" of SPm(hox) during hypoxia. Thus, VEGF/Flt1 signaling may drive the process of a SP cell mediated "stemness switch" during hypoxia.

ISBN: 9780494277195Subjects--Topical Terms:

1018566
Health Sciences, Oncology.

The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis.
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245 1 4 $a The role of VEGF autocrine signaling in hypoxia and oxidative stress driven "stemness switch": Implications in solid tumor progression and metastasis.
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500 $a Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 2971.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2007.
520 $a Tumor hypoxia enhances Vascular endothelial growth factor (VEGF) autocrine/paracrine signaling leading to angiogenic switch, but the role of VEGF in the self-renewal/survival of highly tumorigenic side-population (SP) cells has not been studied. Here I isolated and characterized highly migratory, and tumorigenic fraction of SP cells (SPm(hox)) in several solid tumor cell lines including neuroblastoma, rhabdomyosarcoma, medulloblastoma, and small cell lung carcinoma cell lines and evaluated the role of VEGF in the self-renewal/survival of SPm(hox) during hypoxia in neuroblastoma (SK-N-BE(2)), and rhabdomyosarcoma (RH4) cell lines. Exposure to hypoxia increased the SP fraction by 6-10 fold and SPm(hox) fraction by 2-3 fold in all the cell lines. SPm(hox) cells show very high SDF-1alpha/CXCR4 activity and could be isolated using a modified Boyden Chamber system, migrating in response to a hypoxia/hydrogen peroxide treated bone marrow stromal cell, "injured conditioned medium". In nude mice, significantly fewer (1-5x10 3) SPm(hox) cells form highly angiogenic and rapidly growing subcutaneous tumors and liver metastasis as compared to the original cell line (&sim;5x106). In an in vivo matrigel "stemness" assay, SPm(hox) cells initiate a hypoxic/oxidative-stress condition of repair/regeneration to maintain and enhance the SP-state (stemness). siRNA knockdown of Flt1 reduced the hypoxia-driven SPm(hox) self-renewal by three fold (p=0.03556) and reduced the in vivo homing of SPm(hox) to the "injured bone marrow" by 75% (p=0.0293). In addition, siRNA Flt1 knockdown reduced the hypoxia-induced Oct-4 expressing SPm (hox) cells by five fold (p = 0.0017) suggesting that VEGF/Flt1 signaling may enhance the "stemness" of SPm(hox) during hypoxia. Thus, VEGF/Flt1 signaling may drive the process of a SP cell mediated "stemness switch" during hypoxia.
520 $a Further investigations suggest that chemotherapeutic drug cisplatin treatment can induce the process of "stemness switch" by VEGF/Flt1 signaling leading to tumorigenicity in an non-tumorigenic osteosarcoma cell line, HOS. Functional inhibition of Flt1 signaling completely reduced cisplatin-induced tumorigenicity by reducing the number of SP cells. Further investigation revealed that both hypoxia and drugs led to increased generation of ROS, oxidative stress and subsequent "stemness switch". To further investigate the role of oxidative stress in hypoxia and drug induced "stemness switch" anti-oxidants squalene and n-acetyl cysteine (NAC) were used to reduce drug-induced stemness. Interestingly, both of these antioxidants were protective against cisplatin-induced toxicity of murine BM stem cell fraction. However, both these agents failed to reduce drug-mediated increased SP cell fraction and VEGF secretion. NAC failed to reduce oxidative stress in the tumor cells, and marginally enhanced the drug-induced tumor cell repopulation in vivo, whereas squalene did not show any significant effects. Further investigations revealed that tumor SP cells have very high endogenous level of oxidants compared to normal BM stem cell fraction.
520 $a Taken together, here I demonstrate that VEGF autocrine signaling is involved in the oxidative stress induced "stemness switch". Based on these findings I would like to propose a stem cell model of tumor repair and regeneration where following drug-induced hypoxia, TSCs will be mobilized from the quiescent mode to the repair/regeneration mode ("stemness switch") leading to rapid repopulation of tumor cells. During the course of mobilization, TSCs may recruit autocrine growth signaling such as VEGF signaling for the self renewal of TSCs in their hypoxic niche.
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