The Immunohistochemical Analysis of Antigens such as RCAS1 and B7H4 in the Cervical Cancer Nest and within the Fibroblasts and Macrophages Infiltrating the Cancer Microenvironment

Abstract

Introduction The presence of the aggressive phenotype of the tumor seems to be indicated by the local infiltration of cancer cells and by the development of metastases in the lymph nodes. This phenotype is related to the intensity of the suppressive profile of the tumor microenvironment. The aim of our study has been to gather information about the expression of both RCAS1 and B7H4 proteins in the macrophages and fibroblasts present within both the microenvironment of cervical cancer tumors and the cancer cells present on the front of the cancer nest. Methods We analyzed the immunoreactivity levels of such antigens as B7H4 and RCAS1 in the macrophages and fibroblasts of the cancer microenvironment and within the cancer nest in the tissue samples derived from patients on whom both a radical hysterectomy and a lymphadenectomy had been performed following a diagnosis of uterine cervical carcinoma. These patients were then divided into two subgroups according to the extent of the local and distant advancement of the cancer – that is, according to the FIGO stage and the presence or absence of lymph node metastases. Results RCAS1 immunoreactivity levels on the front of the cancer nest statistically significantly increase according to the FIGO stage or the extent of the local spread of the disease while B7H4 immunoreactivity levels on the tumor front increase in relation to the extent of the distant spread of the disease or the presence of lymph nodes metastases. Conclusion The intensity of the suppressive profile of the cervical cancer microenvironment indicated by the presence of both RCAS1 and B7H4 on the front of the tumor and in the macrophages and fibroblasts infiltrating the cancer stroma seems to correlate with the extent of both the local and distant advancement of the disease.

B7-H4 overexpression correlates with a poor prognosis for cervical cancer patients

“…Similar results were previously reported (20). In addition to tumor cells, tumor-infiltrating macrophages (8,15,21) and the endothelial cells of small blood vessels in the cancer microenvironment were also found to constitutively express B7-H4. B7-H4 was also found to be highly expressed on tumor-associated macrophages in the ascites of ovarian cancer patients and may contribute to tumor progression (15).…”

High post‐treatment serum soluble receptor‐binding cancer antigen expressed on SiSo cells (sRCAS1) levels is associated with poor survival of patients with cervical cancer

“…15 In one of our previous studies, we found that RCAS1 immunoreactivity levels on the front of the cervical cancer nest were positively correlated with both the FIGO stage and with the extent of the local spread, thus indicating a more aggressive phenotype. 31 In the present study, we found no differences in the serum sRCAS1 levels between early and advanced stage cervical cancer patients. This finding accords with the original report by Sonoda et al 7 However, in a different study by the Japanese group, the authors reported that not all RCAS1-expressing cells secreted sRCAS1 to the blood stream.…”

“…In a further study by Sonoda et al ., RCAS1 over‐expression in cervical cancer samples was positively correlated with invasion of the lymph‐vascular space, multiple lymph node metastases and tumor volume . In one of our previous studies, we found that RCAS1 immunoreactivity levels on the front of the cervical cancer nest were positively correlated with both the FIGO stage and with the extent of the local spread, thus indicating a more aggressive phenotype . In the present study, we found no differences in the serum sRCAS1 levels between early and advanced stage cervical cancer patients.…”

The potential predictive value of serum srCaS1 levels for overall survival in endometrial cancer

“…Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) was discovered in 1996 by Sonoda et al [8] as a membrane protein present on cervical cancer cells. RCAS1 expression was found on a variety of cells, including T, B, and NK cells, and on macrophages, fibroblasts, and human neoplastic cells [9]. RCAS1 acts through the putative receptor, and its main function is related to the induction of selective immunosuppression.…”