Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.

Since the first nationwide movement control order was implemented on 18 March 2020 in Malaysia to contain the coronavirus disease 2019 (COVID-19) outbreak, to what extent the uncertainty and continuous containment measures have imposed psychological burdens on the population is unknown. This study aimed to measure the level of mental health of the Malaysian public approximately 2 months after the pandemic’s onset. Between 12 May and 5 September 2020, an anonymous online survey was conducted. The target group included all members of the Malaysian population aged 18 years and above. The Depression Anxiety Stress Scale (DASS-21) was used to assess mental health. There were increased depressive, anxiety and stress symptoms throughout the study period, with the depression rates showing the greatest increase. During the end of the data collection period (4 August–5 September 2020), there were high percentages of reported depressive (59.2%) and anxiety (55.1%) symptoms compared with stress (30.6%) symptoms. Perceived health status was the strongest significant predictor for depressive and anxiety symptoms. Individuals with a poorer health perception had higher odds of developing depression (odds ratio [OR] = 5.68; 95% confidence interval [CI] 3.81–8.47) and anxiety (OR = 3.50; 95%CI 2.37–5.17) compared with those with a higher health perception. By demographics, young people–particularly students, females and people with poor financial conditions–were more vulnerable to mental health symptoms. These findings provide an urgent call for increased attention to detect and provide intervention strategies to combat the increasing rate of mental health problems in the ongoing COVID-19 pandemic.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and includes squamous cell carcinomas of the oropharynx and oral cavity. Patient prognosis has remained poor for decades and molecular targeted therapies are not in routine use. Here we showed that the overall expression of collagen subunit genes was higher in cancer-associated fibroblasts (CAFs) than normal fibroblasts. Focusing on collagen8A1 and collagen11A1, we showed that collagen is produced by both CAFs and tumour cells, indicating that HNSCCs are collagen-rich environments. We then focused on discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, and showed that it is over-expressed in HNSCC tissues. Further, we demonstrated that collagen promoted the proliferation and migration of HNSCC cells and attenuated the apoptotic response to cisplatin. Knockdown of DDR1 in HNSCC cells demonstrated that these tumour-promoting effects of collagen are mediated by DDR1. Our data suggest that specific inhibitors of DDR1 might provide novel therapeutic opportunities to treat HNSCC.

Soke Chee Kwong, Amira Hajirah Abd Jamil, Anthony Rhodes, Nur Aishah Taib, Ivy Chung

Understanding the complex, multistep process of metastasis remains a major challenge in cancer research. Metastasis models can reveal insights in tumor development and progression and provide tools to test new intervention strategies.