Abstract
Background
The transmembrane adapter protein, DAP12, transduces activation signals for several
arrays of receptors, including human signal-regulatory protein, DAP12-associating
lectin-1, triggering receptor expressed on myeloid cells-1, -2, and -3, in natural
killer cells, granulocytes, monocytes/macrophages, and dendritic cells. The macrophage-specific
antigen, Cluster of Differentiation 163 (CD163), is expressed in breast and colorectal
cancers and is associated with early cancer recurrence and poor prognosis. It was
recently shown that fusion between intestinal tumor cells and macrophages results
in nuclear reprogramming with hybrid transcripts from both cells of origin. The role
of DAP12 in the fusion process is not known. This study investigates the expression
of DAP12 in BRC cells, and its relation to other macrophage traits and to the clinical
progression of disease.
Materials and Methods
Immunostaining of DAP12 and CD163 was performed and evaluated in paraffin-embedded
specimens from 132 patients with BRC. The outcomes were analyzed in relation to clinicopathological
data.
Results
DAP12 expression in cancer cells was positive in 66 percent of the cancers and was
associated with high tumor grade (P = .015), and with liver (P = .047) and skeletal (P = .067), but not with lung metastases (P = 1.00). Patients with BRC expressing DAP12 had poor prognosis, with higher recurrence
rates of skeletal (P = .018) and liver metastases (P = .047), and shorter survival time (P = .0060).
Conclusion
We suggest that macrophage traits in BRC cells facilitate the metastatic process and
that DAP12 expression might promote metastatic homing to bone and liver tissues.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Breast CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.Nature. 2003; 425: 968-973
- Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation.Nat Med. 2004; 10: 494-501
- Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion.Nat Cell Biol. 2008; 10: 584-592
- Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer.Dig Liver Dis. 2009; 41: 116-122
- Multiple tumor types may originate from bone marrow-derived cells.Neoplasia. 2006; 8: 716-724
- Bone marrow-derived cells fuse with normal and transformed intestinal stem cells.Proc Natl Acad Sci U S A. 2006; 103: 6321-6325
- Donor Y chromosome in renal carcinoma cells of a female BMT recipient: visualization of putative BMT-tumor hybrids by FISH.Bone Marrow Transplant. 2005; 35: 1021-1024
- Spontaneously formed tumorigenic hybrids of Meth A sarcoma cells and macrophages in vivo.Int J Cancer. 2003; 106: 153-159
- Acquisition of high metastatic capacity after in vitro fusion of a nonmetastatic tumor line with a bone marrow-derived macrophage.J Exp Med. 1984; 160: 1579-1584
- Melanoma x macrophage hybrids with enhanced metastatic potential.Clin Exp Metastasis. 1998; 16: 299-312
- Fusion between intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming.Cancer Res. 2011; 71: 1497-1505
- Tumour-cell fusion as a source of myeloid traits in cancer.Lancet Oncol. 2005; 6: 988-993
- Massive inflammatory syndrome and lymphocytic immunodeficiency in KARAP/DAP12-transgenic mice.Eur J Immunol. 2002; 32: 2653-2663
- DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.J Exp Med. 2003; 198: 669-675
- Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.J Clin Invest. 2003; 111: 323-332
- DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming.Immunity. 2000; 13: 345-353
- Identification of the haemoglobin scavenger receptor.Nature. 2001; 409: 198-201
- Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage.Am J Surg Pathol. 2005; 29: 617-624
- Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends Immunol. 2002; 23: 549-555
- Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.Cell. 2006; 124: 263-266
- Tumour-educated macrophages promote tumour progression and metastasis.Nat Rev Cancer. 2004; 4: 71-78
- Macrophages regulate the angiogenic switch in a mouse model of breast cancer.Cancer Res. 2006; 66: 11238-11246
- Tumor-associated macrophages press the angiogenic switch in breast cancer.Cancer Res. 2007; 67: 5064-5066
- Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy.Eur J Cancer. 2006; 42: 717-727
- Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. Swedish Breast Cancer Cooperative Group.J Natl Cancer Inst. 1996; 88: 1543-1549
- Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival.Int J Cancer. 2008; 123: 780-786
- The measurement of observer agreement for categorical data.Biometrics. 1977; 33: 159-174
- Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.Int J Cancer. 2009; 125: 1826-1831
- Human monocyte x mouse melanoma fusion hybrids express human gene.Gene. 2001; 275: 103-106
- Expression of c-Met proto-oncogene in metastatic macrophage x melanoma fusion hybrids: implication of its possible role in MSH-induced motility.Oncol Res. 2003; 14: 163-174
- Beta1,6-branched oligosaccharides regulate melanin content and motility in macrophage-melanoma fusion hybrids.Melanoma Res. 2007; 17: 9-16
- Fusion hybrids with macrophage and melanoma cells up-regulate N-acetylglucosaminyltransferase V, beta1-6 branching, and metastasis.Cell Growth Differ. 2001; 12: 623-630
- Dissemination and growth of cancer cells in metastatic sites.Nat Rev Cancer. 2002; 2: 563-572
- The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited.Nat Rev Cancer. 2003; 3: 453-458
- Cancer-cell fusion with migratory bone-marrow-derived cells as an explanation for metastasis: new therapeutic paradigms.Future Oncol. 2008; 4: 449-452
- Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis.Nat Rev Cancer. 2008; 8: 377-386
- Spontaneously formed tumorigenic hybrids of Meth A sarcoma and macrophages grow faster and are better vascularized than the parental tumor.Int J Cancer. 2002; 100: 407-413
- The molecular basis of macrophage fusion.Immunobiology. 2007; 212: 785-793
- Essential role of DAP12 signaling in macrophage programming into a fusion-competent state.Sci Signal. 2008; 1 (ra11)
- The TREM-1/DAP12 pathway.Immunol Lett. 2008; 116: 111-116
- TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function.J Bone Miner Res. 2006; 21: 237-245
- Molecular biology of bone metastasis.Mol Cancer Ther. 2007; 6: 2609-2617
- Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy.J Mammary Gland Biol Neoplasia. 2005; 10: 169-180
- Platelet and osteoclast beta3 integrins are critical for bone metastasis.Proc Natl Acad Sci U S A. 2003; 100: 14205-14210
- Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts.J Clin Invest. 2000; 105: 433-440
- Cancer metastasis: building a framework.Cell. 2006; 127: 679-695
- Breast cancer metastasis to bone: it is not all about PTHrP.Clin Orthop Relat Res. 2003; : S39-S45
- Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases.Cancer Res. 2005; 65: 5778-5784
- Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer.N Engl J Med. 2000; 342: 525-533
- Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer.J Natl Cancer Inst. 2005; 97: 1840-1847
- Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma.J Natl Cancer Inst. 1996; 88: 1222-1227
- Prognostic significance of bone marrow micrometastases in patients with gastric cancer.J Clin Oncol. 1996; 14: 1810-1817
- L1 is associated with micrometastatic spread and poor outcome in colorectal cancer.Mod Pathol. 2007; 20: 1183-1190
- Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis.Cancer Res. 2001; 61: 4432-4436
- Osteoprotegerin prevents and reverses hypercalcemia in a murine model of humoral hypercalcemia of malignancy.Cancer Res. 2000; 60: 783-787
Article info
Publication history
Published online: June 28, 2013
Accepted:
May 3,
2013
Received in revised form:
April 30,
2013
Received:
December 17,
2012
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
