A prognostic model comprising pT stage, N status, and the chemokine receptors CXCR4 and CXCR7 powerfully predicts outcome in neoadjuvant resistant rectal cancer patients

Abstract

Despite the optimization of the local treatment of advanced rectal cancer (LARC), combination of preoperative chemoradiotherapy (CRT) and surgery, approximately one third of patients will develop distant metastases. Since the chemokine receptor CXCR4 has been implicated in metastasis development and prognosis in colorectal cancer, the role of the entire axis CXCR4-CXCL12-CXCR7 was evaluated to identify high relapse risk rectal cancer patients. Tumor specimens of 68 LARC patients undergoing surgery after neoadjuvant-CRT were evaluated for CXCR4, CXCR7, and CXCL12 expression through immunohistochemistry. Multivariable prognostic model was developed using classical prognostic factors along with chemokine receptor expression profiles. High CXCR4 correlated with a shorter relapse-free survival (RFS) (p 5 0.0006) and cancer specific survival (CSS) (p 5 0.0004). Concomitant high CXCR4-negative/low CXCR7 or high CXCR4-negative/low CXCL12 significantly impaired RFS (p 5 0.0003 and p 5 0.0043) and CSS (p 5 0.0485 and p 5 0.0026). High CXCR4/N1 identified the worst prognostic category for RFS (p < 0.0001) and CSS (p 5 0.0003). The optimal multivariable predictive model for RFS was a five-variable model consisting of gender, pT stage, N status, CXCR4, and CXCR7 (AUC 5 0.92, 95% CI 5 0.77-0.98). The model is informative and supportive for adjuvant treatment and identifies CXCR4 as a new therapeutic target in rectal cancer.V C 2013 UICC Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe and a leading cause of cancer death worldwide. 1 Approximately thirty percent of colorectal adenocarcinomas arise in the rectum. 1 The adoption of total mesorectal excision (TME) and the transition from postoperative to preoperative treatment have improved the management of

Molecular Pathways: Targeting the CXCR4–CXCL12 Axis—Untapped Potential in the Tumor Microenvironment

“…Initial interest in pursuing the CXCR4-CXCL12 axis as a target for cancer therapy was fueled by observations implicating CXCR4 in promoting metastasis (2,28). CXCR4 is expressed in at least 20 different human cancers (8,(29)(30)(31)(32)(33); CXCR7 is also expressed in tumors and found to be involved in cell growth, survival, and metastasis (34,35). Like CXCR4, it is expressed on tumor-associated vessels and on neovasculature (36).…”

The wound healing, chronic fibrosis, and cancer progression triad

“…In cancer, the SDF-1/CXCR4 axis has been implicated in the progression of several types of malignancies, and its expression is associated with poor prognosis (66,132,387,393,395). An important study almost a decade ago demonstrated that SDF-1 secreted by TAFs (but not normal fibroblastic cells) triggers both angiogenesis and tumor growth via CXCR4 (275).…”

CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients

“…50 Primers used in this study were as follows: GUSB , and CXCL12 were graded as negative/low (0-50%) and high (>50%). 17 For B7-H1/PD-L1, both non-commercial and a commercially available antibodies, mouse monoclonal antibody made in Dr. Lieping Chen's lab, clone 5H1, 1:500 dilution 51,52 and rabbit monoclonal antibody, clone SP142, 1:200 dilution, 44 Spring Bioscience) were used with prior pressure cooker to 110 C £ 10 min Antigen Retrieval (Ventana Medical Systems, Cell Conditioning Solution CC1, pH 9.0). 44 PD-1 was detected with mouse monoclonal antibody PD-1) (Ventana Medical Systems, NAT105).…”

“…16 In locally advanced rectal cancer patients, high CXCR4 correlated with a shorter relapse-free and cancer specific survival and high CXCR4/NC identified the worst prognostic category. 17 Exosomes derived from HT29 human colon cancer cells, increased CXCL12 expression in the metastatic microenvironment, attracting cancer cells and other stromal cells expressing CXCR4. 18 Interaction between CXCR4 and innate immunity were previously reported.…”