MicroRNAs (miRNAs) are involved in the progression of many cancers through largely unelucidated mechanisms. The results of our present study identified a gene cluster, miR‐221/222, that is constitutively upregulated in serum exosome samples of patients with colorectal carcinoma (CRC) with liver metastasis (LM); this upregulation predicts a poor overall survival rate. Using an in vitro cell coculture model, we demonstrated that CRC exosomes harboring miR‐221/222 activate liver hepatocyte growth factor (HGF) by suppressing SPINT1 expression. Importantly, miR‐221/222 plays a key role in forming a favorable premetastatic niche (PMN) that leads to the aggressive nature of CRC, which was further shown through in vivo studies. Overall, our results show that exosomal miR‐221/222 promotes CRC progression and may serve as a novel prognostic marker and therapeutic target for CRC with LM.

The γδ T cell is a promising candidate cell in tumor immunotherapy. However, γδ T cells polarize to CD39 ⁺ γδ Tregs upon colorectal cancer (CRC) induction, and the underlying mechanism remains unclear. Here, we show that the frequency of CD39 ⁺ γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided CRC (RSCRC) than in the left-sided CRC (LSCRC). Interestingly, CD39 ⁺ γδ Tregs from RSCRC showed stronger immunosuppressive phenotype and function than LSCRC. Furthermore, the quantitative mass spectrometry data show that CD39 ⁺ γδ Treg polarization was related to the abnormal activation of the Phospholipase a2-IVa/Arachidonic acid (PLA2G4A/AA) metabolic pathway in RSCRC. Using an in vitro coculture system and an orthotopic murine model of CRC, we show that the overexpression of Pla2g4a in CT26 cells induced CD39 ⁺ γδ Tregs, inhibiting the antitumor immune response. Finally, we found that the overall survival of the PLA2G4A ^hi group was significantly shortened compared with PLA2G4A ^lo RSCRC, while the survival of LSCRC showed the opposite. Collectively, RSCRC with abnormal PLA2G4A expression educates γδ T cells into CD39 ⁺ γδ Tregs to promote tumor progression and metastasis. Our work highlights the interaction between cancer cells and immune cells by distinguishing the primary tumor site and deepens the understanding of the tumor microenvironment and immunosuppression.

Programmed death 1 (PD‑1)‑targeted therapy has benefited patients with microsatellite instability‑high metastatic colorectal cancer (mCRC). However, the efficacy of PD‑1‑targeted therapy is poor in patients with microsatellite‑stable (MSS) mCRC. Therefore, it is imperative to explore additional co‑inhibitory molecular signalling pathways to improve the efficacy of immunotherapy in MSS mCRC treatment. In the present study, the association between cyclin‑dependent kinase 9 (CDK9) expression and the survival of patients with CRC was analysed using RNA sequencing data from 605 patients, including 121 cases of mortality, from human cancer datasets. Furthermore, 35 clinical MSS stage III‑IV CRC specimens were collected to assess CDK9 protein expression by immunohistochemistry, and the frequency of tumor‑infiltrating CD8+ T cells was assessed by flow cytometry. The human cancer datasets demonstrated that upregulation CDK9 significantly shortened the survival of patients with stage II‑IV colon cancer. Additionally, CDK9 mRNA expression was positively correlated with the expression levels of genes associated with immune evasion in the tumor. Notably, CDK9 was expression was upregulated in stage IV CRC compared with para‑cancerous tissues and early‑stage tumors. Interestingly, CDK9 expression was negatively associated with the infiltration of CD8+ T cells at the tumor site. In addition, the expression levels of T‑cell immunoglobulin mucin family member 3 and CD39, proteins associated with exhaustion, on tumor‑infiltrating CD8+ T cells were significantly elevated in patients with abnormal CDK9 expression levels. The present study demonstrated that CDK9 expression was negatively associated with CD8+ T cell infiltration and positively associated with CD8+ T cell exhaustion in MSS mCRC. In conclusion, CDK9 may be utilized to evaluate the prognosis and the immune‑type of the tumor microenvironment in patients with MSS mCRC.

Background and Objectives: An increasing number of studies have shown the influence of primary tumor location of colon cancer on prognosis, but the prognostic difference between colon cancers at different locations remains controversial. After comparing the prognostic differences between left-sided and right-sided colon cancer, the study subdivided left-sided and right-sided colon cancer into three parts, respectively, and explored which parts had the most significant prognostic differences, with the aim to further analyze the prognostic significance of primary locations of colon cancer. Materials and Methods: Clinicopathological data of patients with colon cancer who underwent radical surgery from the Surveillance, Epidemiology, and End Results Program database were analyzed. The data was divided into two groups (2004–2009 and 2010–2015) based on time intervals. Two tumor locations with the most significant survival difference were explored by using Cox regression analyses. The prognostic difference of the two locations was further verified in survival analyses after propensity score matching. Results: Patients with right-sided colon cancer had worse cancer-specific and overall survival compared to left-sided colon cancer. Survival difference between cecum cancer and sigmoid colon cancer was found to be the most significant among six tumor locations in both 2004–2009 and 2010–2015 time periods. After propensity score matching, multivariate analyses showed that cecum cancer was an independent unfavorable factor for cancer specific survival (HR [95% CI]: 1.11 [1.04–1.17], p = 0.001 for 2004–2009; HR [95% CI]: 1.23 [1.13–1.33], p < 0.001 for 2010–2015) and overall survival (HR [95% CI]: 1.09 [1.04–1.14], p < 0.001 for 2004–2009; HR [95% CI]: 1.09 [1.04–1.14], p < 0.001 for 2010–2015) compared to sigmoid colon cancer. Conclusions: The study indicates the prognosis of cecum cancer is worse than that of sigmoid colon. The current dichotomy model (right-sided vs. left-sided colon) may be inappropriate for the study of colon cancer.

BACKGROUND: The characteristics of patients with colorectal cancer who have benign mesenteric lymph node enlargement are not well documented. OBJECTIVE: The aim of this study is to assess the clinical and prognostic significance of benign mesenteric lymph node enlargement in patients with colorectal cancer. DESIGN: This is a prospective cohort study. SETTING: This study was conducted at multitertiary institutions. PATIENTS: We included 601 patients with stage 0, I, and II colorectal cancer in Tianjin, Shandong, and Zhejiang from January 2010 to April 2014. Patients underwent curative surgery and were separated into 2 groups by the presence of benign mesenteric lymph node enlargement: the enlargement group (n = 275) and the control group (n = 326). MAIN OUTCOME MEASURES: Univariate log rank and multivariate Cox regression analyses were constructed to identify risk factors for recurrence and mortality. RESULTS: The risk of recurrence in the enlargement group after curative resection was significantly lower than in the control group, with the 1-, 3-, and 5-year disease-free survival rates being 97.1%, 91.6%, and 86.9% in the enlargement group and 95.7%, 86.2%, and 78.2% in the control group (p = 0.004). The postoperative 1-, 3-, and 5-year overall survival rates were 99.6%, 94.9%, and 90.5% in the enlargement group and 99.4%, 91.4%, and 82.1% in the control group (p = 0.001). Patients in the enlargement group had a higher percentage of patients at a younger age, family tumor history, right-sided tumors, and larger tumor size compared with the control group. For patients in the enlargement group, no significant correlation was observed between the number of enlarged lymph nodes and disease-free survival or overall survival (p = 0.113 and 0.386). Adjusted Cox regression model showed that benign mesenteric lymph node enlargement was an independent prognostic risk factor for both disease-free survival (HR, 0.587; 95% CI, 0.399–0.861; p = 0.007) and overall survival (HR, 0.506; 95% CI, 0.328–0.779; p = 0.002). LIMITATIONS: No immunological results could be compared with clinicopathological findings. CONCLUSIONS: The study indicates that benign mesenteric lymph node enlargement can be a useful positive factor in predicting recurrence and long-term survival concerning patients with colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B785. CARACTERÍSTICAS PRONÓSTICAS DE LOS PACIENTES PORTADORES DE CÁNCER COLORRECTAL CON AGRANDAMIENTO BENIGNO DE LOS GANGLIOS LINFÁTICOS MESENTÉRICOS: UN ESTUDIO DE COHORTE MULTIINSTITUCIONAL: ANTECEDENTES: Las características de los pacientes portadores de cáncer colorrectal con agrandamiento benigno de los ganglios linfáticos mesentéricos no se encuentran bien documentados. OBJETIVO: El objetivo de este estudio es evaluar la importancia clínica y pronóstica del agrandamiento benigno de los ganglios linfáticos mesentéricos en pacientes con cáncer colorrectal. DISEÑO: Este es un estudio de cohorte de tipo prospectivo. AJUSTE: Este estudio se llevó a cabo en instituciones de educación superior. PACIENTES: Incluimos a 601 pacientes con cáncer colorrectal en estadio 0, I, II en Tianjin, Shandong y Zhejiang desde enero de 2010 hasta abril de 2014. Los pacientes fueron sometidos a cirugía curativa y fueron separaron en dos grupos tomando en cuenta la presencia del agrandamiento benigno de los ganglios linfáticos mesentéricos: grupo con agrandamiento (n = 275) y grupo control (n = 326). PRINCIPALES MEDIDAS DE RESULTADO: Se construyeron análisis de rango logarítmico de una variante y de regresión de Cox con variante múltiple para identificar los factores de riesgo de recurrencia y mortalidad. RESULTADOS: El riesgo de recurrencia en el grupo con agrandamiento tras la resección curativa fue significativamente menor que en el grupo de control, con tasas de periodo libre de enfermedad a los 1, 3 y 5 años de 97,1, 91,6, y 86,9% en el grupo de agrandamiento y con tasas de 95,7, 86,2, y 78,2% en el grupo control respectivamente (p = 0,004). Las tasas postoperatorias de supervivencia general a los 1, 3 y 5 años fueron 99,6, 94,9, y 90,5% en el grupo de agrandamiento y de 99,4, 91,4, y 82,1% en el grupo de control, respectivamente (p = 0,001). Los pacientes del grupo con agrandamiento tenían un porcentaje más elevado de menor edad, antecedente familiar tumoral, tumores del lado derecho y de mayor tamaño tumoral con respecto al grupo de control. Para los pacientes con agrandamiento, no se observó una correlación significativa entre el número de ganglios linfáticos agrandados y el periodo libre de enfermedad o la supervivencia general (p = 0,113 y 0,386). El modelo de regresión de Cox ajustado mostró que el agrandamiento benigno de los ganglios linfáticos mesentéricos era un factor de riesgo pronóstico independiente tanto para la supervivencia libre de enfermedad (cociente de riesgo 0,587; IC del 95%: 0,399-0,861; p = 0,007) como para la supervivencia global (cociente de riesgo 0,506; IC del 95%: 0,328- 0,779; p = 0,002). LIMITACIONES: No fue posible comparar los resultados inmunológicos con los hallazgos clínico-patológicos. CONCLUSIONES: El estudio indica que el agrandamiento benigno de los ganglios linfáticos mesentéricos puede ser un factor positivo útil para predecir la recurrencia y la supervivencia a largo plazo en pacientes con cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B785. (Traducción—Dr. Osvaldo Gauto)