Abstract
BackgroundThe intratumoral infiltration of T cells, especially memory T cells, is associated with a favorable prognosis in early colorectal cancers. However, the mechanism underlying this process remains elusive. This study examined whether high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is involved in the infiltration of T cells and disease progression in locally advanced colon cancer.MethodsSeventy-two cases of pathologically-confirmed specimens were obtained from patients with stage IIIB (T3N1M0) colon cancer who underwent radical resection between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University. The density of tumor-infiltrating lymphocytes (TILs) within the tumor tissue and the expression of HMGB1 in the cancer cells were examined via immunohistochemical analysis. The phenotype of CD45RO+ cells was confirmed using a flow cytometric assay. The association between HMGB1 expression, the density of TILs, and the 5-year survival rate were analyzed.ResultsThe density of CD45RO+ T cells within the tumor was independently prognostic, although a higher density of CD3+ T cells was also associated with a favorable prognosis. More importantly, the expression of HMGB1 was observed in both the nucleus and the cytoplasm (co-expression pattern) in a subset of colon cancer tissues, whereas nuclear-only expression of HMGB1 (nuclear expression pattern) existed in most of the cancer tissues and normal mucosa. The co-expression pattern of HMGB1 in colon cancer cells was inversely associated with the infiltration of both CD3+ and CD45RO+ T cells and 5-year survival rates.ConclusionsThis study revealed that the co-expression of HMGB1 is inversely associated with the infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer, indicating that the distribution patterns of HMGB1 might contribute to the progression of colon cancer via modulation of the local immune response.
Highlights
The intratumoral infiltration of T cells, especially memory T cells, is associated with a favorable prognosis in early colorectal cancers
Colorectal cancers are characterized by infiltration with multiple stromal cells, among which are tumorinfiltrating lymphocytes (TILs) that act as prognostic and predictive factors [6,7,8,9,10,11,12,13,14,15]
Patterns of TIL infiltration and high-mobility group box 1 (HMGB1) expression within stage IIIB colon cancer tissues CD3+ and CD45RO+ cells were observed in all cases in the tumor stroma and the adjacent normal mucosa different extents
Summary
Materials Seventy-two cases of pathologically-confirmed specimens matched with adjacent normal mucosa were obtained from patients with stage IIIB (T3N1M0; AJCC, 2002) colon cancer between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University in Guangzhou, China (Table 1). After blocking with sheep serum, the sections were incubated overnight at 4°C with either rabbit polyclonal antibody against human HMGB1 at a dilution of 1:1000 (Abcam, Cambridge, MA, USA) or mouse monoclonal antibody against human CD3, CD45RO, CD4, CD8, and CD56 All of these antibodies (Zymed, San Diego, CA, USA) were diluted 1:100. After blocking nonspecific binding with goat serum, the sections were incubated overnight at 4°C with a rabbit anti-human HMGB1 polyclonal antibody (1:1000; Abcam, Cambridge, MA, USA) and a mouse anti-human CD45RO monoclonal antibody (1:100; Zymed, San Diego, CA, USA) simultaneously. The following factors were assessed with both univariate and multivariate analyses to determine their influence on overall survival: gender, age, pathologic grade, tumor site, the density of CD3+ cells, the density of CD45RO+ cells, and the level or subcellular location of HMGB1 expression within colon cancer tissues. Statistical significance was assumed for a twotailed P < 0.05
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