Colorectal cancer, spy protein: reveals how it will evolve and customises treatment

What should I expect? This is the question most frequently asked by people facing colon and rectal cancer, trying to unlock the secrets of the disease's prognosis. In the future, perhaps a 'spy' protein, identifiable in healthy cells present in the tumour microenvironment, could help to answer it. As if that were not enough, the information derived from this invisible beacon could prove extremely useful in therapeutic terms, helping specialists to identify patients who could most benefit from immunotherapy or treatments aimed at inhibiting specific targets involved in the proliferation of neoplastic cells.

The protein in question is called CTHRC1. And the cells that express it, becoming invisible 'treasure troves' of knowledge for oncologists, are CTHRC1(+) CAFs. They are part of a population of tumour-associated fibroblasts, the CAFs in fact, connective tissue cells that are part of the altered cancer microenvironment and that, instead of fighting the tumour, promote its development. Uncovering these realities, shaping knowledge for the future, is a study that appeared inGut conducted by a multidisciplinary team of pathologists, oncologists and biologists from the Hospital del Mar Research Institute (HMRIB), the Institute for Research in Biomedicine (IRB Barcelona) and the CIBER Oncology Area (CIBERONC).

The journey into the invisible by Iberian experts (first author Mar Iglesias), including Alexandre Calon, coordinator of the Translational Research Group on the Tumour Microenvironment at the Hospital del Mar Research Institute and Clara Montagut, oncologist at the Hospital del Mar, started by studying the potential of CTHRC1(+) CAFs as predictive markers of treatment response in samples of almost 3.000 patients. By then exploring the RNA of tumour cells, the researchers identified the most interesting cellular markers as possible 'markers' of tumour characteristics to determine the proteins they expressed. At the end of the process, therefore, they came to realise that CTHRC1 itself is a spy protein that can be expressed by fibroblasts in the tumour microenvironment - CAF CTHRC1(+) - and that it constitutes a biomarker for defining a tumour as 'immunologically warm', i.e. sensitive to immunotherapy, or 'cold', i.e. resistant to immunotherapy. These laboratory observations have in fact been validated on samples of patients undergoing different treatments at numerous centres, leading Calon to say in a note that 'the validated marker maintains a high predictive and prognostic capacity in different patient cohorts'.

The 'spy' protein somehow also becomes strategic in defining what can be expected in the individual patient in terms of disease evolution. The CAF marker CTHRC1 is in fact associated with high activity of a cytokine in the tumour microenvironment. It is called TGF-beta and is generally associated with a less favourable prognosis. This also raises the possibility of targeting drugs that act in combination as both inhibitors of the protein itself and of TFG-beta in the future, although we are only at the beginning. What is important is that we have added to our knowledge of the role that the tumour microenvironment plays on the evolution of the picture and the response to treatment. One of the authors, Eduard Batlle, a researcher at the IRB in Barcelona and a member of CIBERONC, recalls how over the years 'research has shown that TGF-beta is a key regulator of this ecosystem, modulating the behaviour of the stromal cells that surround the tumour. The identification of CTHRC1 as a TGF-beta-induced factor exemplifies how basic research can lead to clinically applicable biomarkers'.

The results of the study could finally increase the appropriateness of the use of immunotherapy in this form of cancer, increasing the possible prospects for its use, given that the approach is currently only proposed for a very small percentage of patients. The research shows that the presence of CAF CTHRC1(+) makes it possible to determine the status of the immune cells within the tumour and their ability to act against the neoplastic cells. 'This biomarker improves the selection of patients who could potentially benefit from immunotherapy,' Clara Montagut commented. 'These observations could help guide therapeutic strategies for colon and rectal cancer patients. Moreover, the results could be applicable to other tumour types, such as breast and lung cancer.