The tumour microenvironment consists of a complex mixture of non-neoplastic cells, including fibroblasts, immune cells and endothelial cells embedded in the proteins of the extracellular matrix. The tumour microenvironment plays an active role in tumour behaviour. By interacting with cancer cells, it influences disease progression and the metastatic capacity of the tumour. Tumours with a high amount of stroma correspond to poor patient prognosis. The tumour-stroma ratio (TSR) is a strong independent prognostic tool in colon cancer and provides additional value to the current clinically used tumour-node-metastasis classification. The TSR is assessed on conventional haematoxylin and eosin-stained paraffin sections at the invasive front of the tumour. Here we review studies demonstrating the prognostic significance of the TSR in solid epithelial tumours with a focus on colon cancer. Moreover, the biological role of the tumour microenvironment during tumour progression and invasion will be discussed, as well as the attempts to target the tumour stroma for therapeutic purposes. We suggest that the TSR can be implemented with little effort and without additional costs in current routine pathology diagnostics owing to its simplicity and reliability.

Background The tumor microenvironment has a critical role in regulating cancer cell behavior. Tumors with high stromal content are associated with poor patient outcome. The tumor-stroma ratio (TSR) identifies colorectal cancers (CRC) with poor patient prognosis based on hematoxylin & eosin stained sections. The desmoplastic reaction consists to a great extent of cancer-associated fibroblasts (CAFs) of which different subtypes are known. The aim of this study is to investigate and quantify CAFs present in the tumor stroma of CRC stratified by the TSR to possibly add prognostic significance to the TSR. Methods The expression of established CAF markers was compared between stroma-low and stroma-high tumors using transcriptomic data of 71 stage I – III CRC. Based on literature, fibroblast and stromal markers were selected to perform multiplex immunofluorescent staining on formalin fixed, paraffin-embedded tumor sections of patients diagnosed with stage III colon cancer. Antibodies against the following markers were used: αSMA, PDGFR -β, FAP, FSP1 and the stromal markers CD45 and CD31 as reference. The markers were subsequently quantified in the stroma using the Vectra imaging microscope. Results The transcriptomic data showed that all CAF markers except one were higher expressed in stroma-high compared to stroma-low tumors. Histologically, stroma-high tumors showed a decreased number of FSP1 + /CD45 + cells and a trend of an increased expression of FAP compared to stroma-low tumors. FAP was higher expressed at the invasive part compared to the tumor center in both stroma-high and stroma-low tumors. Conclusions The increased expression of FAP at the invasive part and in stroma-high tumors might contribute to the invasive behavior of cancer cells. Future functional experiments should investigate the contribution of FAP to cancer cell invasion. Combining the quantity of the stroma as defined by the TSR with the activity level of CAFs using the expression of FAP may result in an expanded stroma-based tool for patient stratification. Electronic supplementary material The online version of this article (10.1186/s12885-019-5462-2) contains supplementary material, which is available to authorized users.

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt–luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies. © 2015 Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Striatal dopamine (DA) is central to reward-based learning. Less is known about the contribution of DA to the ability to adapt previously learned behavior in response to changes in the environment, such as a reversal of response-reward contingencies. We hypothesized that DA is involved in the rapid updating of response-reward information essential for successful reversal learning. We trained rats to discriminate between two levers, where lever availability was signaled by a non-discriminative cue. Pressing one lever was always rewarded, whereas the other lever was never rewarded. After reaching stable discrimination performance, a reversal was presented, so that the previously non-rewarded lever was now rewarded and vice versa. We used fast-scan cyclic voltammetry to monitor DA release in the ventromedial striatum. During discrimination performance (pre-reversal), cue presentation induced phasic DA release, whereas reward delivery did not. The opposite pattern was observed post-reversal: Striatal DA release emerged after reward delivery, while cue-induced release diminished. Trial-by-trial analysis showed rapid reinstatement of cue-induced DA release on trials immediately following initial correct responses. This effect of positive feedback was observed in animals that learned the reversal, but not in 'non-learners'. In contrast, neither pre-reversal responding and DA signaling, nor post-reversal DA signaling in response to negative feedback differed between learners and non-learners. Together, we show that phasic DA dynamics in the ventromedial striatum encoding reward-predicting cues are associated with positive feedback during reversal learning. Furthermore, these signals predict individual differences in learning that are not present prior to reversal, suggesting a distinct role for dopamine in the adaptation of previously learned behavior.