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Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer.

Owusu BY, Vaid M, Kaler P, Klampfer L - Biomark Cancer (2015)

Bottom Line: Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in.Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs.In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA.

ABSTRACT
Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment. Recent advances in the understanding of the involvement of the tumor microenvironment in tumor progression and therapeutic response are optimizing the application of prognostic and predictive factors in colon cancer. Moreover, new targets in the tumor microenvironment that are amenable to therapeutic intervention have been identified. Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs. In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

No MeSH data available.


Related in: MedlinePlus

Macrophages promote 5FU-induced apoptosis. (A) HCT116 and HKe-3 cells were treated with 5FU (10 μM) in the absence or the presence of THP1 macrophages (Mo) or IL-1β as indicated and the extent of apoptosis was determined after 48 hours. (B) HCT116 cells were treated with 5FU (1 μM or 10 μM) in the absence or the presence of THP1 macrophages or IL-1β as indicated for 48 hours. Cell lysates were examined for the presence of cleaved PARP, cleaved caspase-7, p53, and p21 by immunoblotting.
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f3-bic-suppl.1-2015-029: Macrophages promote 5FU-induced apoptosis. (A) HCT116 and HKe-3 cells were treated with 5FU (10 μM) in the absence or the presence of THP1 macrophages (Mo) or IL-1β as indicated and the extent of apoptosis was determined after 48 hours. (B) HCT116 cells were treated with 5FU (1 μM or 10 μM) in the absence or the presence of THP1 macrophages or IL-1β as indicated for 48 hours. Cell lysates were examined for the presence of cleaved PARP, cleaved caspase-7, p53, and p21 by immunoblotting.

Mentions: Macrophages modulate the response to therapy by producing soluble factors, including IL-6, TNF, IL-1β, and IL-17, which activate prosurvival signaling pathways, such as STAT3, Wnt, and NFκB, in cancer cells. We described that macrophages protect colon cancer cells from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by promoting Wnt signaling in colon cancer cells.14,116 Inactivation of β or silencing of β in macrophages inhibited their ability to counter TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (ΔΨ) and activation of caspases were prevented by macrophages or by recombinant β. However, macrophages can also enhance the response to therapy. For example, we demonstrated that macrophages and IL-1β actually promote 5-fluorouracil (5FU)-induced apoptosis in colon cancer cells (Fig. 3A; Kaler and Klampfer, unpublished data). The presence of macrophages (Mo) or treatment with IL-1β increased the response to 5FU (Fig. 3A), confirmed by enhanced activation of caspase-7 and cleavage of Poly (ADP-ribose) polymerase (PARP) (Fig. 3B). These findings are in line with a complex role of macrophages in colon cancer.


Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer.

Owusu BY, Vaid M, Kaler P, Klampfer L - Biomark Cancer (2015)

Macrophages promote 5FU-induced apoptosis. (A) HCT116 and HKe-3 cells were treated with 5FU (10 μM) in the absence or the presence of THP1 macrophages (Mo) or IL-1β as indicated and the extent of apoptosis was determined after 48 hours. (B) HCT116 cells were treated with 5FU (1 μM or 10 μM) in the absence or the presence of THP1 macrophages or IL-1β as indicated for 48 hours. Cell lysates were examined for the presence of cleaved PARP, cleaved caspase-7, p53, and p21 by immunoblotting.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4631158&req=5

f3-bic-suppl.1-2015-029: Macrophages promote 5FU-induced apoptosis. (A) HCT116 and HKe-3 cells were treated with 5FU (10 μM) in the absence or the presence of THP1 macrophages (Mo) or IL-1β as indicated and the extent of apoptosis was determined after 48 hours. (B) HCT116 cells were treated with 5FU (1 μM or 10 μM) in the absence or the presence of THP1 macrophages or IL-1β as indicated for 48 hours. Cell lysates were examined for the presence of cleaved PARP, cleaved caspase-7, p53, and p21 by immunoblotting.
Mentions: Macrophages modulate the response to therapy by producing soluble factors, including IL-6, TNF, IL-1β, and IL-17, which activate prosurvival signaling pathways, such as STAT3, Wnt, and NFκB, in cancer cells. We described that macrophages protect colon cancer cells from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by promoting Wnt signaling in colon cancer cells.14,116 Inactivation of β or silencing of β in macrophages inhibited their ability to counter TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (ΔΨ) and activation of caspases were prevented by macrophages or by recombinant β. However, macrophages can also enhance the response to therapy. For example, we demonstrated that macrophages and IL-1β actually promote 5-fluorouracil (5FU)-induced apoptosis in colon cancer cells (Fig. 3A; Kaler and Klampfer, unpublished data). The presence of macrophages (Mo) or treatment with IL-1β increased the response to 5FU (Fig. 3A), confirmed by enhanced activation of caspase-7 and cleavage of Poly (ADP-ribose) polymerase (PARP) (Fig. 3B). These findings are in line with a complex role of macrophages in colon cancer.

Bottom Line: Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in.Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs.In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA.

ABSTRACT
Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment. Recent advances in the understanding of the involvement of the tumor microenvironment in tumor progression and therapeutic response are optimizing the application of prognostic and predictive factors in colon cancer. Moreover, new targets in the tumor microenvironment that are amenable to therapeutic intervention have been identified. Because stromal cells are with rare exceptions genetically stable, the tumor microenvironment has emerged as a preferred target for therapeutic drugs. In this review, we discuss the role of stromal fibroblasts and macrophages in colon cancer progression and in the response of colon cancer patients to therapy.

No MeSH data available.


Related in: MedlinePlus