Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.

Background: Methods: Results: Conclusion:

Higher-grade inflammatory infiltrate is a promising marker for better prognosis in colorectal cancer (CRC). However, the knowledge on the interrelationships between different inflammatory cells and classifications is fragmentary. We analysed the densities of eight types of inflammatory cells in a prospectively recruited group of 117 CRC patients and determined their interrelationships and contributions to Klintrup–Mäkinen (K–M) score of overall peritumoural inflammation. We characterised the inflammatory infiltrate in relation to stage and recurrences in 24-month follow-up. There were high positive correlations between the inflammatory cell densities, with the exception of mast cells and CD1a⁺ immature dendritic cells. High K–M score associated with high peri- and intratumoural densities of CD3⁺, CD8⁺, CD68⁺, CD83⁺, and FoxP3⁺ cells and neutrophils. Advanced stage associated with low K–M score, as well as low CD3⁺, CD8⁺, CD83⁺, and FoxP3⁺ cell counts, of which low K–M score, low CD3⁺ T-cell count, and low FoxP3⁺ T-cell count were linked to higher recurrence rate. The density of CRC inflammatory infiltrate declines as stage advances. Especially, low K–M score and low T-cell counts predict higher recurrence rate. The high positive correlations between the individual inflammatory markers support the value of overall inflammatory reaction scoring.

Anemia is common in colorectal cancer (CRC) but its relationships with tumor characteristics, systemic inflammation, and survival have not been well characterized. In this study, blood hemoglobin levels and erythrocyte mean corpuscular volume (MCV) levels were measured in two independent cohorts of 148 CRC patients and 208 CRC patients, and their correlation with patient and tumor characteristics, systemic inflammatory markers (modified Glasgow Prognostic Score: mGPS; serum levels of thirteen cytokines, C-reactive protein, albumin), and survival were analyzed. We found that anemia, most frequently normocytic, followed by microcytic, was present in 43% of the patients. Microcytic anemia was most commonly associated with proximal colon tumor location. Average MCV and blood hemoglobin levels were lower in tumors with high T-class. Low blood hemoglobin associated with systemic inflammation, including high mGPS and high serum levels of C-reactive protein and IL-8. Particularly, normocytic anemia associated with higher mGPS. Normocytic anemia associated with a tendency towards worse overall survival (multivariate hazard ratio 1.61, 95% confidence interval 1.07–2.42, p = 0.023; borderline statistical significance considering multiple hypothesis testing). In conclusion, anemia in CRC patients is most frequently normocytic. Proximal tumor location is associated with predominantly microcytic anemia and systemic inflammation is associated with normocytic anemia.

A subset of colorectal cancers (CRCs) exhibits so‐called Crohn's like lymphoid reaction (CLR), an inflammatory reaction pattern that consists of numerous transmural lymphoid aggregates. However, the composition of these aggregates, their biological mechanisms and their prognostic significance are not well‐defined. We analyzed two CRC cohorts (418 and 149 patients) and determined clinicopathological features including survival. A new method for evaluating CLR based on counting the areal density of the lymphoid follicles (CLR density) was adopted. Immune cell densities at intratumoral and peritumoral regions, as well as the composition of the lymphoid follicles, were studied by immunohistochemistry. We found that CLR comprised of lymphoid aggregates with no evidence of granuloma formation. High CLR density associated with lower tumor stage, lack of preoperative radiotherapy or chemoradiotherapy and deficient mismatch repair enzyme expression. CLR density had positive correlations with peritumoral and intratumoral densities of CD83⁺ mature dendritic cells and T cells. High CLR density associated with better survival and had prognostic value that was independent of stage, Klintrup‐Mäkinen score for peritumoral inflammation and the numbers of tumor infiltrating T cells. CLR density evaluation had excellent intraobserver and interobserver agreement. In conclusion, the results suggest that CLR contributes to the adaptive antitumor immunity. Quantitative evaluation of CLR density is a relevant prognostic indicator in CRC.

Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.