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Notch and TGFβ: Functional partners facilitating tumor progression.

Ohnuki H, Tosato G - Oncoimmunology (2014)

Bottom Line: Cell signals integral to the tumor microenvironment influence cancer progression.Tumor-associated myeloid cells secrete pro-tumorigenic agents including, but not limited to, the potent cytokine transforming growth factor β (TGFβ).We have discovered a network of extrinsic signals including delta-like 4 (Dll4), Notch and TGFβ, linking malignant cells and tumor-infiltrating myeloid cells, a nexus portending a clinically-relevant anticancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Oncology; Center for Cancer Research; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.

ABSTRACT
Cell signals integral to the tumor microenvironment influence cancer progression. Tumor-associated myeloid cells secrete pro-tumorigenic agents including, but not limited to, the potent cytokine transforming growth factor β (TGFβ). We have discovered a network of extrinsic signals including delta-like 4 (Dll4), Notch and TGFβ, linking malignant cells and tumor-infiltrating myeloid cells, a nexus portending a clinically-relevant anticancer treatment.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Proposed model of interaction between carcinoma cells and tumor-infiltrating monocytes. Lewis lung carcinoma (LLC1) tumor cells express the delta-like (Dll) Notch ligands Dll1 and Dll4 and all variants of Notch receptors (Notch1–4). Tumor-infiltrating monocytes express the Notch ligand Dll4 and secrete transforming growth factor β (TGFβ). In situations in which the cancer cell density is high, Notch signaling is predominantly induced in the tumor cells through tumor-intrinsic cell-to-cell interactions. At the infiltrating edge of the tumor where tumor density is low, Dll4-expressing monocytes present in the tumor microenvironment activate Notch signaling in the cancer cells. TGFβ signaling in the cancerous cells and TGFβ tumor growth stimulation are magnified by convergent Notch signaling.
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Figure 1: Figure 1. Proposed model of interaction between carcinoma cells and tumor-infiltrating monocytes. Lewis lung carcinoma (LLC1) tumor cells express the delta-like (Dll) Notch ligands Dll1 and Dll4 and all variants of Notch receptors (Notch1–4). Tumor-infiltrating monocytes express the Notch ligand Dll4 and secrete transforming growth factor β (TGFβ). In situations in which the cancer cell density is high, Notch signaling is predominantly induced in the tumor cells through tumor-intrinsic cell-to-cell interactions. At the infiltrating edge of the tumor where tumor density is low, Dll4-expressing monocytes present in the tumor microenvironment activate Notch signaling in the cancer cells. TGFβ signaling in the cancerous cells and TGFβ tumor growth stimulation are magnified by convergent Notch signaling.

Mentions: In contrast to LLC1 cells in culture, LLC1-derived tumors in vivo are prominently infiltrated by pro-tumorigenic CD11b+Ly6C+Ly6G- monocytes, recruited and activated by the tumor-derived cytokines, chemokine (C-C motif) ligand 2 (Ccl2) and colony stimulating factor 1 (Csf1, best known as M-CSF). We found that these tumor-infiltrating monocytes secrete abundant TGFβ that, in turn, induces Smad signaling within the LLC1 tumor. Furthermore, these myeloid cells express Dll4 at high levels, even higher than those expressed by LLC1 cells. This monocyte-associated Dll4 is anticipated to activate Notch signaling within the tumor microenvironment in which monocytes and tumor cells engage. Indeed, treatment of LLC1 tumor-bearing mice with the γ-secretase inhibitor DAPT reduced Notch and TGFβ signaling within the tumor and reduced tumor growth. Since this antitumor effect was lacking in functionally monocyte-deficient mutant mice, collectively, these results show that tumor-infiltrating monocytes are critical inducers of Notch signaling within the tumor, and that TGFβ accelerates LLC1 progression by cooperating with Notch signaling. In this scenario, tumor-promoting monocytes play a dual role as both a source of TGFβ as well as inducers of Notch signaling among tumor cells (Fig. 1). This role would be most detrimental at the infiltrating edge of the tumor, a locale where monocyte cluster and tumor cell density is low, as monocytes would be essential inducers of Notch signaling in cells comprising the tumor mass.


Notch and TGFβ: Functional partners facilitating tumor progression.

Ohnuki H, Tosato G - Oncoimmunology (2014)

Figure 1. Proposed model of interaction between carcinoma cells and tumor-infiltrating monocytes. Lewis lung carcinoma (LLC1) tumor cells express the delta-like (Dll) Notch ligands Dll1 and Dll4 and all variants of Notch receptors (Notch1–4). Tumor-infiltrating monocytes express the Notch ligand Dll4 and secrete transforming growth factor β (TGFβ). In situations in which the cancer cell density is high, Notch signaling is predominantly induced in the tumor cells through tumor-intrinsic cell-to-cell interactions. At the infiltrating edge of the tumor where tumor density is low, Dll4-expressing monocytes present in the tumor microenvironment activate Notch signaling in the cancer cells. TGFβ signaling in the cancerous cells and TGFβ tumor growth stimulation are magnified by convergent Notch signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 1: Figure 1. Proposed model of interaction between carcinoma cells and tumor-infiltrating monocytes. Lewis lung carcinoma (LLC1) tumor cells express the delta-like (Dll) Notch ligands Dll1 and Dll4 and all variants of Notch receptors (Notch1–4). Tumor-infiltrating monocytes express the Notch ligand Dll4 and secrete transforming growth factor β (TGFβ). In situations in which the cancer cell density is high, Notch signaling is predominantly induced in the tumor cells through tumor-intrinsic cell-to-cell interactions. At the infiltrating edge of the tumor where tumor density is low, Dll4-expressing monocytes present in the tumor microenvironment activate Notch signaling in the cancer cells. TGFβ signaling in the cancerous cells and TGFβ tumor growth stimulation are magnified by convergent Notch signaling.
Mentions: In contrast to LLC1 cells in culture, LLC1-derived tumors in vivo are prominently infiltrated by pro-tumorigenic CD11b+Ly6C+Ly6G- monocytes, recruited and activated by the tumor-derived cytokines, chemokine (C-C motif) ligand 2 (Ccl2) and colony stimulating factor 1 (Csf1, best known as M-CSF). We found that these tumor-infiltrating monocytes secrete abundant TGFβ that, in turn, induces Smad signaling within the LLC1 tumor. Furthermore, these myeloid cells express Dll4 at high levels, even higher than those expressed by LLC1 cells. This monocyte-associated Dll4 is anticipated to activate Notch signaling within the tumor microenvironment in which monocytes and tumor cells engage. Indeed, treatment of LLC1 tumor-bearing mice with the γ-secretase inhibitor DAPT reduced Notch and TGFβ signaling within the tumor and reduced tumor growth. Since this antitumor effect was lacking in functionally monocyte-deficient mutant mice, collectively, these results show that tumor-infiltrating monocytes are critical inducers of Notch signaling within the tumor, and that TGFβ accelerates LLC1 progression by cooperating with Notch signaling. In this scenario, tumor-promoting monocytes play a dual role as both a source of TGFβ as well as inducers of Notch signaling among tumor cells (Fig. 1). This role would be most detrimental at the infiltrating edge of the tumor, a locale where monocyte cluster and tumor cell density is low, as monocytes would be essential inducers of Notch signaling in cells comprising the tumor mass.

Bottom Line: Cell signals integral to the tumor microenvironment influence cancer progression.Tumor-associated myeloid cells secrete pro-tumorigenic agents including, but not limited to, the potent cytokine transforming growth factor β (TGFβ).We have discovered a network of extrinsic signals including delta-like 4 (Dll4), Notch and TGFβ, linking malignant cells and tumor-infiltrating myeloid cells, a nexus portending a clinically-relevant anticancer treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Oncology; Center for Cancer Research; National Cancer Institute; National Institutes of Health; Bethesda, MD USA.

ABSTRACT
Cell signals integral to the tumor microenvironment influence cancer progression. Tumor-associated myeloid cells secrete pro-tumorigenic agents including, but not limited to, the potent cytokine transforming growth factor β (TGFβ). We have discovered a network of extrinsic signals including delta-like 4 (Dll4), Notch and TGFβ, linking malignant cells and tumor-infiltrating myeloid cells, a nexus portending a clinically-relevant anticancer treatment.

No MeSH data available.


Related in: MedlinePlus