Consensus molecular subtypes of colorectal cancer in clinical practice: A translational approach

Colorectal cancer (CRC) is a major cause of cancer-related deaths globally. While treatment advancements have improved survival rates, primarily through targeted therapies based on KRAS, NRAS, and BRAF mutations, personalized treatment strategies for CRC remain limited. Immunotherapy, mainly immune checkpoint blockade, has shown efficacy in various cancers but is effective in only a small subset of patients with CRC with deficient mismatch repair (dMMR) proteins or high microsatellite instability (MSI). Recent research has challenged the notion that CRC is immunologically inert, revealing subsets with high immunogenicity and diverse lymphocytic infiltration. Identifying precise biomarkers beyond dMMR and MSI is crucial to expanding immunotherapy benefits. Hence, exploration has extended to various biomarker sources, such as the tumor microenvironment, genomic markers, and gut microbiota. Recent studies have introduced a novel classification system, consensus molecular subtypes, that aids in identifying patients with CRC with an immunogenic profile. These findings underscore the necessity of moving beyond single biomarkers and toward a comprehensive understanding of the immunological landscape in CRC, facilitating the development of more effective, personalized therapies.

Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia–reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of cancer to achieve their application in human medicine.

Reactive oxygen species (ROS) play a physiological role in the modulation of several functions of the vascular wall; however, increased ROS have detrimental effects. Hence, oxidative stress has pathophysiological impacts on the control of the vascular tone and cardiac functions. Recent experimental studies reported the involvement of increased ROS in the mechanism of hypertension, as this disorder associates with increased production of pro-oxidants and decreased bioavailability of antioxidants. In addition, increased ROS exposure is found in ischemia-reperfusion, occurring in acute myocardial infarction and cardiac surgery with extracorporeal circulation, among other settings. Although these effects cause major heart damage, at present, there is no available treatment. Therefore, it should be expected that antioxidants counteract the oxidative processes, thereby being suitable against cardiovascular disease. Nevertheless, although numerous experimental studies agree with this notion, interventional trials have provided mixed results. A better knowledge of ROS modulation and their specific interaction with the molecular targets should contribute to the development of novel multitarget antioxidant effective therapeutic strategies. The complex multifactorial nature of hypertension, acute myocardial infarction, and postoperative atrial fibrillation needs a multitarget antioxidant strategy, which may give rise to additive or synergic protective effects to achieve optimal cardioprotection.

MAP4K4 is a serine/threonine kinase that belongs to the MAP kinase family and plays a critical role in embryogenesis and cellular migration. It contains approximately 1,200 amino acids and has a molecular mass of 140 kDa. MAP4K4 is expressed in most tissues where it has been examined and its knockout is embryonic lethal due to impaired somite development. Alterations in MAP4K4 function have a central role in the development of many metabolic diseases such as atherosclerosis and type 2 diabetes, but have recently been implicated in the initiation and progression of cancer. For example, it has been shown that MAP4K4 can stimulate the proliferation and invasion of tumor cells by activating pro-proliferative pathways (such as the c-Jun N-terminal kinase [JNK] and mixed-lineage protein kinase 3 [MLK3] pathways), attenuate anti-tumor cytotoxic immune responses, and stimulate cell invasion and migration by altering cytoskeleton and actin function. Recent in vitro experiments using RNA interference-based knockdown (miR) techniques have shown that inhibition of MAP4K4 function reduces tumor proliferation, migration, and invasion, and may represent a promising therapeutic approach in many types of cancer such as pancreatic cancer, glioblastoma, and medulloblastoma, among others. Over the last few years, specific MAP4K4 inhibitors such as GNE-495 have been developed but have not yet been tested in cancer patients. However, these novel agents may be useful for cancer treatment in the future.

Cancer patient care requires a multi-disciplinary approach and multiple medical and ethical considerations. Clinical care during a pandemic health crisis requires prioritising the use of resources for patients with a greater chance of survival, especially in developing countries. The coronavirus disease 2019 crisis has generated new challenges given that cancer patients are normally not prioritised for admission in critical care units. Nevertheless, the development of new cancer drugs and novel adjuvant/neoadjuvant protocols has dramatically improved the prognosis of cancer patients, resulting in a more complex decision-making when prioritising intensive care in pandemic times. In this context, it is essential to establish an effective and transparent communication between the oncology team, critical care, and emergency units to make the best decisions, considering the principles of justice and charity. Concurrently, cancer treatment protocols must be adapted to prioritise according to oncologic response and prognosis. Communication technologies are powerful tools to optimise cancer care during pandemics, and we must adapt quickly to this new scenario of clinical care and teaching. In this new challenging pandemic scenario, multi-disciplinary work and effective communication between clinics, technology, science, and ethics is the key to optimising clinical care of cancer patients.