Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.

Purpose: Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course RT (LCRT; 25 × 1.8 Gy) with concomitant chemotherapy and short-course RT (SCRT; 5 × 5 Gy), typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different RT regimens in LARC. Experimental Design: We conducted a serial sampling study involving patients receiving RT for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA sequencing of tumor biopsies were used to assess local changes. Results: Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared with SCRT patients at week 6 (P < 0.0001) and week 12 (P = 0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared with LCRT patients at week 2 (CD8 P = 0.053; FOXP3 P = 0.023) and week 6 (CD8 P = 0.035; FOXP3 P = 0.0016). Conclusions: SCRT is less lymphodepleting and induces more frequent increases in intratumoral T-cell infiltration compared with LCRT. These results are relevant to the field of radiation–immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, in which higher rates of response to RT–immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.

Background: Tumour budding (TB), defined as a small cluster of up to four cells at the invasive front of the tumour, is a well-established independent and robust prognostic biomarker in colorectal cancer (CRC). This is strongly associated with adverse clinicopathological features and poor survival outcomes. Despite its clinical relevance, the precise underlying mechanism responsible for TB phenomenon remains unclear. Methods: Multi-omic approaches from bulk, regional GeoMx and Spatial Molecular Imager (SMI) RNA were used to identify the underlying mechanism of TB and its possible correlation with tumour microenvironment (TME) in CRC tissue. The results were validated using immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) staining. Results: Patients with high TB experience worse outcomes and associate with adverse clinical factors across two independent CRC cohorts. Bulk and regional RNA expression analyses reveal that tumours with high TB are significantly enriched for TNF-α and TGF-β signatures in both cohorts. Single cell CosMx SMI analysis confirmed TB cells exhibit higher expression of these signatures than adjacent invasive edge tumour cells. Elevated cyclinD1 expression was also observed within TB, and high cyclinD1 levels tend to experience poorer CRC prognosis. Furthermore, regional bulk RNA expression within the non-tumour (PanCK-) invasive edge areas demonstrated that tumours exhibiting high TB revealed the significantly differential expressions of immune-related genes (e.g. CD3 , NKG7 , IL6 , CXCR6 , CD47 , IFNAR1 and VSIR ). Single cell CosMx SMI analysis revealed that cancer-associated fibroblasts (CAFs) were physically the closest cells to TB cells. This spatial proximity was confirmed at the protein level using mIF, where the distance from TB to CD68+ macrophages predicted significantly poorer CRC outcomes. Conclusion: This multi-omic study confirms the prognostic significance of TB in CRC patients across two independent cohorts. Our findings highlight that TNF-α and TGF-β signalling play a crucial role in budding cells development by regulating cyclinD1. Furthermore, the transcriptomic analysis reveals an immunosuppressive niche characterised by reduced immune activity and close spatial interactions with CAFs and macrophages Ultimately, this study provides valuable insight into TB’s underlying mechanism and its complex interactions within the TME. This could provide a foundation for developing targeted therapeutic strategies in CRC.

Introduction: Insulin‐like growth factor 1 (IGF‐1)/IGF‐1 receptor (IGF‐1R) signalling is activated in breast cancer and associated with disease progression. Pregnancy‐associated plasma protein‐A (PAPP‐A) is a metalloproteinase that can cleave IGF binding proteins leading to the release of bioactive IGF‐1 and the subsequent activation of IGF‐1 signalling. Here, we aimed to assess the prognostic significance of PAPP‐A in breast cancer. Methods: Breast cancer tissue microarrays were stained for PAPP‐A and expression correlated with survival and other clinical features. Analysis of publicly available data sets was carried out to determine associations between PAPPA and gene sets associated with IGF‐1/IGF‐1R pathway activation. Results: PAPP‐A was expressed in both the tumour and stromal compartments in breast cancer specimens and was higher in oestrogen receptor (ER)‐negative (ER‐) than ER‐positive (ER+) cases. There was a significant association between high PAPP‐A expression and reduced cancer‐specific survival (CSS) in ER+ (HR 1.389, 95% CI 1.051–1.836, p = 0.021) but not ER‐ patients (HR 1.040, 95% CI 0.712–1.598, p = 0.838). In a second cohort of ER+ invasive lobular carcinoma (ILC) PAPP‐A expression was also associated with reduced CSS (HR 1.765, 95% CI 1.098–2.836, p = 0.019). PAPPA correlated with REACTOME PI3K‐AKT and IGF1R signalling gene sets in ER+ breast cancers. Conclusion: High expression of PAPP‐A is associated with poor prognosis in ER+ breast cancer and correlates with IGF‐1/IGF‐1R pathway activation.

Study representativeness table