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CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.

Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW - J. Exp. Med. (2015)

Bottom Line: Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice.Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions.These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.

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Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.

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Loss of CCL3 in stromal cells suppresses pulmonary metastasis of human and mouse breast cancer cells. (A) Oncomine search results for CCL3 are shown. (left) CCL3 transcript abundance in stroma of breast cancer (Ca) and normal tissue (N). P = 2.61 × 10-16; fold change, 3.078. (right) CCL3 levels in basal-like (Bs) and luminal-like (Lm) invasive breast carcinoma showing increase in basal cancers. P = 2.28 × 10-4; fold change, 1.747. (B) Lung metastatic burden from orthotopic mammary tumors was quantified (n = 3/genotype, 3 independent experiments). The tumors were developed by MDA231:4175TGL human breast cancer cells in nude mice transplanted with Rag2−/− or Ccl3−/−Rag2−/− BM cells. Plots show normalized photon flux in the lung over time. Data are means ± SEM. *, P < 0.05. Representative images of mice at 35 wk are shown (right). (C) Representative H&E stained microscopy images of the lung from PyMT (n = 8) and PyMT:Ccl3−/− (n = 7) mice with spontaneous metastatic foci (Arrowheads) are shown. Bars, 1 mm. (D) Number and size of lung metastatic foci (left) and primary tumor weights (right) were assessed in autochthonous PyMT (n = 8) or PyMT:Ccl3−/− mice (n = 7) at 27–30 wk of age (4 independent experiments). Data are means ± SEM. *, P < 0.01.
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fig3: Loss of CCL3 in stromal cells suppresses pulmonary metastasis of human and mouse breast cancer cells. (A) Oncomine search results for CCL3 are shown. (left) CCL3 transcript abundance in stroma of breast cancer (Ca) and normal tissue (N). P = 2.61 × 10-16; fold change, 3.078. (right) CCL3 levels in basal-like (Bs) and luminal-like (Lm) invasive breast carcinoma showing increase in basal cancers. P = 2.28 × 10-4; fold change, 1.747. (B) Lung metastatic burden from orthotopic mammary tumors was quantified (n = 3/genotype, 3 independent experiments). The tumors were developed by MDA231:4175TGL human breast cancer cells in nude mice transplanted with Rag2−/− or Ccl3−/−Rag2−/− BM cells. Plots show normalized photon flux in the lung over time. Data are means ± SEM. *, P < 0.05. Representative images of mice at 35 wk are shown (right). (C) Representative H&E stained microscopy images of the lung from PyMT (n = 8) and PyMT:Ccl3−/− (n = 7) mice with spontaneous metastatic foci (Arrowheads) are shown. Bars, 1 mm. (D) Number and size of lung metastatic foci (left) and primary tumor weights (right) were assessed in autochthonous PyMT (n = 8) or PyMT:Ccl3−/− mice (n = 7) at 27–30 wk of age (4 independent experiments). Data are means ± SEM. *, P < 0.01.

Mentions: Although the role of CCL3 in breast cancer metastasis remains unclear, oncomine search results (Farmer et al., 2005; Finak et al., 2008) indicated that CCL3 was up-regulated in breast cancer stroma and in basal-like invasive breast carcinoma that are predicted to have poor prognoses (Fig. 3 A). These results suggest that stromal expression of CCL3 is involved in breast cancer progression. To investigate the role of CCL3 in breast cancer metastasis, we injected MDA-MB-231:4175 cells expressing luciferase (Minn et al., 2005) into the mammary fat pad of nude mice as a model for human triple negative breast cancer. The recipient nude mice were irradiated and transplanted with BM cells from immunodeficient mice (Rag2−/−) or those that are homozygous for the Ccl3- allele (Rag2−/−Ccl3−/−) before tumor implantation so that we could investigate the role of CCL3 from BM cells. 4 wk after tumor injection, we resected the primary tumor and determined tumor loads in the lung by in vivo bioluminescence imaging. In support of our hypothesis, the spontaneous pulmonary metastases from the orthotopic 4175 tumors were markedly suppressed by Ccl3 deficiency (Fig. 3 B). To confirm this result in a spontaneous tumor-developing GEM model, we introduced the Ccl3- allele to the PyMT mice on a BL6 background and found that the number of lung metastasis foci was significantly lower in PyMT:Ccl3−/− than PyMT:Ccl3+/+ mice (Fig. 3, C and D). As we could not find significant differences in the size of foci or weight of primary tumors (Fig. 3 D), CCL3 appears to be required for metastatic seeding of cancer cells rather than their growth at the primary and metastatic sites.


CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages.

Kitamura T, Qian BZ, Soong D, Cassetta L, Noy R, Sugano G, Kato Y, Li J, Pollard JW - J. Exp. Med. (2015)

Loss of CCL3 in stromal cells suppresses pulmonary metastasis of human and mouse breast cancer cells. (A) Oncomine search results for CCL3 are shown. (left) CCL3 transcript abundance in stroma of breast cancer (Ca) and normal tissue (N). P = 2.61 × 10-16; fold change, 3.078. (right) CCL3 levels in basal-like (Bs) and luminal-like (Lm) invasive breast carcinoma showing increase in basal cancers. P = 2.28 × 10-4; fold change, 1.747. (B) Lung metastatic burden from orthotopic mammary tumors was quantified (n = 3/genotype, 3 independent experiments). The tumors were developed by MDA231:4175TGL human breast cancer cells in nude mice transplanted with Rag2−/− or Ccl3−/−Rag2−/− BM cells. Plots show normalized photon flux in the lung over time. Data are means ± SEM. *, P < 0.05. Representative images of mice at 35 wk are shown (right). (C) Representative H&E stained microscopy images of the lung from PyMT (n = 8) and PyMT:Ccl3−/− (n = 7) mice with spontaneous metastatic foci (Arrowheads) are shown. Bars, 1 mm. (D) Number and size of lung metastatic foci (left) and primary tumor weights (right) were assessed in autochthonous PyMT (n = 8) or PyMT:Ccl3−/− mice (n = 7) at 27–30 wk of age (4 independent experiments). Data are means ± SEM. *, P < 0.01.
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fig3: Loss of CCL3 in stromal cells suppresses pulmonary metastasis of human and mouse breast cancer cells. (A) Oncomine search results for CCL3 are shown. (left) CCL3 transcript abundance in stroma of breast cancer (Ca) and normal tissue (N). P = 2.61 × 10-16; fold change, 3.078. (right) CCL3 levels in basal-like (Bs) and luminal-like (Lm) invasive breast carcinoma showing increase in basal cancers. P = 2.28 × 10-4; fold change, 1.747. (B) Lung metastatic burden from orthotopic mammary tumors was quantified (n = 3/genotype, 3 independent experiments). The tumors were developed by MDA231:4175TGL human breast cancer cells in nude mice transplanted with Rag2−/− or Ccl3−/−Rag2−/− BM cells. Plots show normalized photon flux in the lung over time. Data are means ± SEM. *, P < 0.05. Representative images of mice at 35 wk are shown (right). (C) Representative H&E stained microscopy images of the lung from PyMT (n = 8) and PyMT:Ccl3−/− (n = 7) mice with spontaneous metastatic foci (Arrowheads) are shown. Bars, 1 mm. (D) Number and size of lung metastatic foci (left) and primary tumor weights (right) were assessed in autochthonous PyMT (n = 8) or PyMT:Ccl3−/− mice (n = 7) at 27–30 wk of age (4 independent experiments). Data are means ± SEM. *, P < 0.01.
Mentions: Although the role of CCL3 in breast cancer metastasis remains unclear, oncomine search results (Farmer et al., 2005; Finak et al., 2008) indicated that CCL3 was up-regulated in breast cancer stroma and in basal-like invasive breast carcinoma that are predicted to have poor prognoses (Fig. 3 A). These results suggest that stromal expression of CCL3 is involved in breast cancer progression. To investigate the role of CCL3 in breast cancer metastasis, we injected MDA-MB-231:4175 cells expressing luciferase (Minn et al., 2005) into the mammary fat pad of nude mice as a model for human triple negative breast cancer. The recipient nude mice were irradiated and transplanted with BM cells from immunodeficient mice (Rag2−/−) or those that are homozygous for the Ccl3- allele (Rag2−/−Ccl3−/−) before tumor implantation so that we could investigate the role of CCL3 from BM cells. 4 wk after tumor injection, we resected the primary tumor and determined tumor loads in the lung by in vivo bioluminescence imaging. In support of our hypothesis, the spontaneous pulmonary metastases from the orthotopic 4175 tumors were markedly suppressed by Ccl3 deficiency (Fig. 3 B). To confirm this result in a spontaneous tumor-developing GEM model, we introduced the Ccl3- allele to the PyMT mice on a BL6 background and found that the number of lung metastasis foci was significantly lower in PyMT:Ccl3−/− than PyMT:Ccl3+/+ mice (Fig. 3, C and D). As we could not find significant differences in the size of foci or weight of primary tumors (Fig. 3 D), CCL3 appears to be required for metastatic seeding of cancer cells rather than their growth at the primary and metastatic sites.

Bottom Line: Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice.Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions.These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets.

View Article: PubMed Central - HTML - PubMed

Affiliation: MRC Centre for Reproductive Health, Queen's Medical Research Institute, the University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.

Show MeSH
Related in: MedlinePlus