Macrophage antigen expression in breast and colorectal cancers : A consequence of macrophage - tumour cell fusion?

Abstract: Carcinogenesis is a sophisticated biological process consisting of a series of progressive changes in somatic cells from premalignant to malignant phenotype. Despite the vast information available about cancer cells, the origin of cancer and cause of metastasis still remain enigmatic. The hypothesis of cell fusion is one of several models explaining the evolution of neoplasia into clinically significant cancer. This theory states that cancer cells through heterotypic fusion with host cells generate hybrids expressing traits from both parental cells, and acquire metastatic potentials and growth-promoting properties. The cell fusion theory is still unproven and speculative, but cell fusion is a common biological process in normal tissue. Accumulated evidence shows that macrophage-cancer cell fusion occurs in vitro and in vivo and produces hybrids with metastatic potential, but the clinical significant of cell fusion is unclear. The aim of this thesis is to test this hypothesis in clinical patient materials and to explore the clinical significance of macrophage phenotype traits in solid tumours.Paraffin-embedded cancer and normal tissue specimens from patients with breast cancer (n=133) and colorectal cancer (two different patient materials with totally 240 patients) were immunostained for the macrophage-specific antigen, CD163. The expression of CD163 was tested in relation to macrophage infiltration and tumour stage, survival time, irradiation, DNA ploidy, cancer cell proliferation and apoptosis.Phenotypic macrophage traits, such as the expression of CD163, were seen in both breast and colorectal cancers, and were correlated to advanced tumour stages and poor survival. CD163 expression was more frequent in rectal cancer after irradiation and was associated with decreased apoptosis. Cancer cell proliferation was correlated to both macrophage infiltration and CD163 expression. Multivariate analysis showed that CD163 is a significant prognostic factor in both breast and colorectal cancers.In an attempt to examine factors related to the function of macrophage fusion, the expression of the signalling adaptor protein DAP12 was tested and related to CD163 expression in breast cancers from 133 patients. DAP12 was shown to occur in breast cancer cells and was related to high histologic tumour grade, skeletal and liver metastasis, and poor prognosis. The findings in this thesis support the cell fusion theory and illustrate its clinical impact on tumour progression and metastasis.