Background: Extracellular matrix (ECM) is remodeled during carcinogenesis. An abundant constituent of ECM is collagen. Type I collagen is secreted by fibroblasts, is important for tumor growth and epithelial‐mesenchymal transition, and may also be secreted by cancer cells. However, the role and function of cancer‐derived Type I collagen in the tumor microenvironment remains unclear.Methods: We used immunohistochemistry and Western blot to detect Type I collagen expression in non‐small cell lung cancer (NSCLC) and esophageal squamous cell carcinoma (ESCC) cell lines, respectively. We assessed the migration and adhesion capability of these cells in vivo by inhibiting Type I collagen in tumors. Relevant data were extracted from a large cohort study of The Cancer Genome Atlas to analyze messenger RNA levels. Protein expression of Type I collagen was further determined in tumor tissues of patients using tissue microarray.Results: Cancer cell lines secreted Type I collagen. The molecular weight of cancer‐derived Type I collagen was different from that secreted by cancer‐associated fibroblasts and normal fibroblasts. Expression levels of COL1A1 and COL1A2 (subtypes of Type I collagen) messenger RNA in NSCLC and ESCC tumors were higher than in normal tissues, but were not associated with tumor node metastasis stages. Low expression of Type I collagen was significantly associated with poor overall survival and cancer cell differentiation.Conclusion: NSCLC and ESCC cells could produce Type I collagen endogenously, revealing the potential functions of Type I collagen in cancer development. Cancer‐derived Type I collagen was associated with overall survival and cancer cell differentiation.

Background: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown. Methods: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis. Results: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110β, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110β deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110β. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110β level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice. Conclusions: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency.

Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo. CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.

Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.

The connections between cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) is critical in cancer initiation, progression, metastasis, and therapy resistance, making it a focal point in cancer theragnosis. This review provides a panorama of associations and regulation pathways between CSCs and EMT, highlighting their significance in cancer. The molecular mechanisms underlined EMT are thoroughly explored, including the involvement of key transcription factors and signaling pathways. In addition, the roles of CSCs and EMT in tumor biology and therapy resistance, is further examined in this review. The clinical implications of CSCs-EMT interplay are explored, including identifying mesenchymal-state CSC subpopulations using advanced research methods and developing targeted therapies such as inhibitors and combination treatments. Overall, understanding the reciprocal relationship between EMT and CSCs holds excellent potential for informing the development of personalized therapies and ultimately improving patient outcomes.