CD44 is a transmembrane glycoprotein. When the CD44 gene is expressed, its pre-messenger RNA (mRNA) can be alternatively spliced into mature mRNAs that encode several CD44 isoforms. The mRNA assembles with ten standard exons, and the sixth variant exon encodes CD44v6, which engages in a variety of biological processes, including cell growth, apoptosis, migration, and angiogenesis. Mechanistically, CD44v6 interacts with hyaluronic acid (HA) or osteopontin, or it acts as a coreceptor for various cytokines, such as epidermal growth factor, vascular endothelial growth factor, hepatocyte growth factor, and C-X-C motif chemokine 12. In this context, the receptor tyrosine kinase or G protein-coupled receptor-associated signaling pathways, including mitogen-activated protein kinase/extracellular-signal-regulated kinase and phosphoinositide-3-kinase/Akt, are activated. Using these actions, homeostasis or regeneration can be facilitated among normal tissues. However, overexpression of the mature mRNA encoding CD44v6 can induce cancer progression. For example, CD44v6 assists colorectal cancer stem cells in colonization, invasion, and metastasis. Overexpression of CD44v6 predicts poor prognosis in patients with colorectal cancer, as patients with a large number of CD44v6-positive cells in their tumors are generally diagnosed at late stages. Thus, the clinical significance of CD44v6 in colorectal cancer deserves consideration. Preclinical results have indicated satisfactory efficacies of anti-CD44 therapy among several cancers, including prostate cancer, pancreatic cancer, and gastric cancer. Moreover, clinical trials aiming to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and toxicity of a commercialized anti-CD44 monoclonal antibody developed by Roche (RO5429083) have been conducted among patients with CD44-expressing malignant tumors, and a clinical trial focusing on the dose escalation of this antibody is ongoing. Thus, we are hopeful that anti-CD44 therapy will be applied in the treatment of colorectal cancer in the future.

Colorectal cancer occurrence and progression involve multiple aspects of host immune deficiencies. In these events, immune cells vary their phenotypes and functions over time, thus enabling the immune microenvironment to be “tumor-inhibiting” as well as “tumor-promoting” as a whole. Because of the association of tumoricidal T cell infiltration with favorable survival in cancer patients, the Immunoscore system was established. Critically, the tumoral Immunoscore serves as an indicator of CRC patient prognosis independent of patient TNM stage and suggests that patients with high Immunoscores in their tumors have prolonged survival in general. Accordingly, stratifications according to tumoral Immunoscores provide new insights into CRC in terms of comparing disease severity, forecasting disease progression, and making treatment decisions. An important application of this system will be to shed light on candidate selection in immunotherapy for CRC, because the T cells responsible for determining the Immunoscore serve as responders to immune checkpoint inhibitors. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration of cytotoxic and memory T cells, while information concerning the survival and function of these cells is still absent. Moreover, other infiltrates, such as dendritic cells, macrophages, and B cells, can still influence CRC prognosis, implying that those might also influence the therapeutic efficacy of immune checkpoint inhibitors. On these bases, this review is designed to introduce the Immunoscore system by presenting its clinical significance and application in CRC.

Lung adenocarcinomas exhibit various patterns of genomic alterations. During the development of this cancer, KRAS serves as a driver oncogene with a relatively high mutational frequency. Emerging data suggest that lung adenocarcinomas with KRAS mutations can show enhanced PD-L1 expression and additional somatic mutations, thus linking the prospect of applying immune checkpoint blockade therapy to this disease. However, the responses of KRAS-mutant lung adenocarcinomas to this therapy are distinct, which is largely attributed to the heterogeneity in the tumoral immune milieus. Recently, it was revealed that KRAS-mutant lung adenocarcinomas simultaneously expressing either a LKB1 or TP53 mutation typically have different immune profiles of their tumours: tumours with a KRAS/TP53 co-mutation generally present with a significant upregulation of PD-L1 expression and tumoricidal T-cell accumulation, and those with a KRAS/LKB1 co-mutation are frequently negative for PD-L1 expression and have few tumoricidal immune infiltrates. In this regard, interrogating TP53 or LKB1 mutation in addition to PD-L1 expression will be promising in guiding clinical use of immune checkpoint blockade therapy for KRAS-mutant lung adenocarcinomas.

Since radiotherapy is widely used in managing thoracic tumors, physicians have begun to realize that radiation-induced lung injury (RILI) seriously limits the effects of radiotherapy. Unfortunately, there are still no effective methods for controlling RILI. Over the last few decades numerous studies have reported the beneficial effects of mesenchymal stem cells (MSCs) on tissue repair and regeneration. MSCs can not only differentiate into lung alveolar epithelial cells and secrete anti-inflammatory factors, but they also deliver some vehicles for gene therapy in repairing the injured lung, which provides new ideas for managing RILI. Thus, many scientists have attempted to manage RILI using MSC-based therapy. However, as a novel therapy MSCs still face various limitations. Herein, we shed light on the current understanding of MSC-based therapy for RILI, including the feasibility, molecular mechanisms, animal studies, and clinical research of MSC-based therapy for RILI. We also present an overview of RILI and MSCs.

Chemotherapy- or radiotherapy-related intestinal microbial dysbiosis is one of the main causes of intestinal mucositis. Cases of bacterial translocation into peripheral blood and subsequent sepsis occur as a result of dysfunction in the intestinal barrier. Evidence from recent studies depicts the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis, which creates an imbalance between beneficial and harmful bacteria in the gut. Decreases in beneficial bacteria can lead to a weakening of the resistance of the gut to harmful bacteria, resulting in robust activation of proinflammatory signaling pathways. For example, lipopolysaccharide (LPS)-producing bacteria activate the nuclear transcription factor-κB signaling pathway through binding with Toll-like receptor 4 on stressed epithelial cells, subsequently leading to secretion of proinflammatory cytokines. Nevertheless, various studies have found that the omega-3 (n–3) polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid and eicosapentaenoic acid can reverse intestinal microbial dysbiosis by increasing beneficial bacteria species, including Lactobacillus, Bifidobacterium, and butyrate-producing bacteria, such as Roseburia and Coprococcus. In addition, the n–3 PUFAs decrease the proportions of LPS-producing and mucolytic bacteria in the gut, and they can reduce inflammation as well as oxidative stress. Importantly, the n–3 PUFAs also exert anticancer effects in colorectal cancers. In this review, we summarize the characteristics of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis and introduce the contributions of dysbiosis to the pathogenesis of intestinal mucositis. Next, we discuss how n–3 PUFAs could alleviate chemotherapy- or radiotherapy-related intestinal microbial dysbiosis. This review provides new insights into the clinical administration of n–3 PUFAs for the management of chemotherapy- or radiotherapy-related intestinal microbial dysbiosis.

Radiation-induced damage is a common occurrence in cancer patients who undergo radiotherapy. In this setting, radiation-induced damage can be refractory because the regeneration responses of injured tissues or organs are not well stimulated. Mesenchymal stem cells have become ideal candidates for managing radiation-induced damage. Moreover, accumulating evidence suggests that exosomes derived from mesenchymal stem cells have a similar effect on repairing tissue damage mainly because these exosomes carry various bioactive substances, such as miRNAs, proteins and lipids, which can affect immunomodulation, angiogenesis, and cell survival and proliferation. Although the mechanisms by which mesenchymal stem cell-derived exosomes repair radiation damage have not been fully elucidated, we intend to translate their biological features into a radiation damage model and aim to provide new insight into the management of radiation damage.