Affiliations: [a] Internal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil | [b] Pathology and Legal Medicine Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil | [c] Surgery and Anatomy Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
Correspondence:
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Corresponding author: Fernanda Maris Peria, Avenida dos Bandeirantes, 3900, Hospital das Clinicas, 6° andar, Departamento Clinica Medica da FMRP-USP, Campus USP Ribeirão Preto, Bairro Monte Alegre. Cidade: Ribeirão Preto. Estado: São Paulo, Pais, Brasil. Tel.: +55 16 3602 2304; E-mail:[email protected]
Abstract: INTRODUCTION: Multiple stages of carcinogenesis in colon cancer
encompass subpopulations of cancer stem cells (CSC), responsible for tumor
cell transformation, growth and proliferation. CD44 and CD166 proteins are
CSC markers associated with cell signaling, adhesion, migration, metastasis
and lymphocytic response. The expression of CSC may be modulated by some
factors, such as the KRAS gene mutation. OBJECTIVE: Correlate the expression of CD44 and CD166 markers in
metastatic colon adenocarcinoma and KRAS mutation status (wild-type/mutated)
with clinical pathological features and patients' outcome. MATERIAL AND METHODS: Fifty-eight samples of tumor tissue samples
of metastatic colon adenocarcinoma were collected from patients treated with
CapeOx at the HCFMRP-USP Clinical Oncology Service. Clinical and survival
data were collected from medical records. KRAS status was determined by the
polymerase chain reaction (PCR) technique, and analysis of
immunohistochemical expression of CD44 and CD166 proteins was performed by
tissue microarray. RESULTS: The expression of CD44 and CD166 were positive in 41%
and 43% of patients, respectively, and mutated KRAS was detected in
48% of patients. A significant association was found between CD166 and
CD44 expression (p= 0.016), mainly in the wild-type KRAS group (p= 0.042) and
patients over 65 years (p= 0.001). CD44-positive patients had 3.7-fold and
5.3-fold greater risk of liver metastasis and lung metastasis, respectively
(p< 0.01), compared with CD44-negative patients. CD166-negative patients had
2.7 greater risk of lymph node involvement (0.03), compared with
CD166-positive patients. KRAS mutation increased the risk of liver
metastasis by 8 times (p< 0.01), and the risk of lung metastasis by 5 times
(p= 0.04) in CD44-positive patients. KRAS mutation increased the risk of
lymph node involvement by 8 times in CD166-negative patients (p= 0.0007). CONCLUSION: An association between CD44 and CD166 expression was
demonstrated in this study. Analysis of KRAS mutation combined with
immunohistochemical expression of CD44 and CD166 identified subgroups of
patients with colon adenocarcinoma at higher risk of lymph node involvement
by the tumor and development of liver and lung metastasis.
Keywords: Colon cancer, KRAS mutation, cancer stem cell, biomarker
