The influence of tumor surrounding microenvironment is often neglected when immunohistochemistry is performed to investigate tumor properties and search biomarkers of cancer. This study was designed to evaluate whether the influence of tumor microenvironment on biological features of tumor cells should be taken into account for interpretation of the immunohistochemistry data of tumor specimens. In this study, we showed an example by using three tumor cell lines (HeLa, WSU-HN6, and Tca83) to establish tumor-caused bone destruction models in nude mice and then to investigate the influence of bone marrow microenvironment (BMM) on biological features of tumor cells. Immunohistochemistry results showed that, compared with tumor cells located outside of BMM, tumor cells located inside of BMM presented huge differences in the expression of inflammation-related proteins including tumor necrosis factor-α (TNF-α), TNF receptor-associated factor protein-6 (TRAF-6), phosphorylated-NF-κB p65 (p-p65), interleukin (IL)-6 and IL-11, matrix metalloproteinases including MMP-1, MMP-2, MMP-9, and MMP-13; and osteogenesis-related proteins including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), and osteocalcin (OCN) in all the models. However, when we compared the cell line pair derived from different sites (outside and inside of BMM, respectively) of the same HeLa tumor sample by real-time PCR, Western blot, and immunocytochemistry, the differences aforementioned in tumor tissues were not found. In addition, we verified that normal human bone marrow could not cause the above changes detected in vivo. Our results suggested that tumor-modified microenvironment could give the new biological features of the invaded tumor cells. Therefore, we should consider the influence of the surrounding microenvironment on tumor cells when we analyze tumor properties using immunohistochemistry.