Intermediate Monocytes but Not TIE2-Expressing Monocytes Are a Sensitive Diagnostic Indicator for Colorectal Cancer

Abstract

We have conducted the first study to determine the diagnostic potential of the CD14++CD16+ intermediate monocytes as compared to the pro-angiogenic subset of CD14++CD16+TIE2+ TIE2-expressing monocytes (TEMs) in cancer. These monocyte populations were investigated by flow cytometry in healthy volunteers (N = 32) and in colorectal carcinoma patients with localized (N = 24) or metastatic (N = 37) disease. We further determined blood levels of cytokines associated with monocyte regulation. The results revealed the intermediate monocyte subset to be significantly elevated in colorectal cancer patients and to show the highest frequencies in localized disease. Multivariate regression analysis identified intermediate monocytes as a significant independent variable in cancer prediction. With a cut-off value at 0.37% (intermediate monocytes of total leukocytes) the diagnostic sensitivity and specificity ranged at 69% and 81%, respectively. In contrast, TEM levels were elevated in localized cancer but did not differ significantly between groups and none of the cytokines correlated with monocyte subpopulations. Of interest, in vitro analyses supported the observation that intermediate monocytes were more potently induced by primary as opposed to metastatic cancer cells which may relate to the immunosuppressive milieu established in the advanced stage of metastatic disease. In conclusion, intermediate monocytes as compared to TIE2-expressing monocytes are a more sensitive diagnostic indicator of colorectal cancer.

Chemotherapy of colorectal liver metastases induces a rapid rise in intermediate blood monocytes which predicts treatment response

“…11,12 Importantly, there were no significant differences in the gene expression profiles between monocyte subsets isolated from healthy controls and mCRC patients, even though we have previously shown that the frequency of subpopulations differs significantly between healthy individuals and mCRC patients. 16 Furthermore, chemotherapy did not alter the gene expression profile of monocyte subsets in mCRC patients. We therefore conclude that the presence (and therapy) of a tumor affects the frequency of monocyte subsets without changing their functional phenotype or identity in terms of characteristic transcript pattern.…”

“…In line, when we previously compared TEM frequency in the blood of CRC patients and healthy individuals, no significant difference was detected. 16 While this finding may be specific to the respective tumor entity, 27 it might also relate to the lower frequency of TEMs (as compared to intermediate monocytes) and hence detection limit in circulation. Since it was previously demonstrated in mouse models that pro-angiogenic, myeloid cell populations could confer resistance to anti-VEGF cancer therapy by providing substitute growth factors, 28,29 it was feasible to hypothesize that bevacizumab treatment might alter TEM frequency to compensate for the loss in VEGF activity.…”

“…It should be noted, though, that this is not merely a function of preferential transmigration but also a differentiation from classical to intermediate monocytes in response to the tumorderived signals as we have previously reported. 16 When subsetspecific gene expression was analyzed for regulators of monocyte migration and invasion, intermediate monocytes did not exhibit a favorable MMP/TIMP balance. Again, this conclusion is restricted to the investigated set of genes.…”

“…15 We have previously reported that intermediate monocytes (as opposed to classical and non-classical monocytes) are specifically increased in CRC patients when compared to healthy individuals. 16 The intermediate subset of TEMs showed a comparable tendency but was not significantly elevated. Given the pro-inflammatory as well as pro-angiogenic properties of intermediate monocytes, their role in malignant disease seems paradoxical, as they may exert both, pro-and antitumor effects.…”

“…For example, an accumulation of TEMs at the tumor site has recently been reported to mediate resistance to antiangiogenic (anti-VEGF) cancer treatment 17 and may be altered by the therapy. 18 Based on our previous study demonstrating a selective rise and a marker potential of intermediate monocytes in CRC patients, 16 we further hypothesized that CRC therapy has an impact on the frequency and function of intermediate monocytes (and possibly the TEM subset). Thus, we aimed to: (1) define the phenotypical and functional properties of intermediate monocytes from mCRC patients and (2) investigate if these properties are affected by neoadjuvant chemotherapy with or without the addition of the VEGF inhibitor bevacizumab (Avastin Ò ).…”