Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy

Carcinoma-associated fibroblasts(CAFs) function as a double-edged sword in tumor progression. However,factors affecting the transition between tumor promotion and inhibition remain to be investigated. Here, we found that the transition was determined by stiffness heterogeneity of the tumor stroma in which tumor cells and CAFs were grown.When tumor cells were grown on a rigid plastic substrate,supernatants from CAFs inhibited the cytotoxic effects of 5-fluorouracil. In contrast, when tumor cells were grown on a soft substrate(5.3 kPa), supernatants from CAFs grown on a soft substrate increased the cytotoxicity of 5-fluorouracil. The diverse effects of CAFs were mediated by mechanotransduction factors, including stroma stiffness-induced cytokine expression in CAFs and signal transduction associated with stress fiber formation of CAFs. Moreover, we found that the cytokine expression in CAFs was regulated by nuclear Yesassociated protein, which changed according to cell stiffness,as characterized by atomic force microscopy. Overall, these findings suggested that modulating the mechanotransduction of the stroma together with CAFs might be important for increasing the efficacy of chemotherapy.

Dynamic role of myofibroblasts in oral lesions

Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts(MFs). MFs are spindle-shaped cells with stress fibres and welldeveloped fibronexus,and they display α-smooth muscle actin immunohistochemically and smoothmuscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources,they play pivotal roles not only by synthesizing and producing extracellular matrix components,such as other connective tissue cells,but also are involved in force production. In the tissue remodelling phase of wound closure,integrinmediated interactions between MFs and type I collagen result in scar tissue formation. The tumour stroma in oral cancer actively recruits various cell types into the tumour mass,where they act as different sources of MFs. This article reviews the importance of MFs and its role in pathological processes such as wound healing,odontogenic cysts and tumours,salivary gland tumours,oral preneoplasia,and oral squamous cell carcinoma. Research oriented on blocking the transdifferentiation of fibroblasts into MFs can facilitate the development of noninvasive therapeutic strategies for the treatment of fibrosis and/or cancer.

THE STUDY OF COLORECTAL CARCINOMA ASSOCIATED ANTIGEN LEA IN CLINICAL PATHOLOGICAL DIAGNOSIS

Objective: To study the expression and the clinical significance of LEA in colorectal carcinoma. Methods: Immunohistochemistry S-P method to detect the expression of LEA and CEA in 140 colorectal cancer specimens and 100 non-cancerous colorectal specimens. Results: The expression of LEA is relative to tumor differentiation degree and exhibits higher selectivity in well-differentiated adeno-carcinoma (P<0.01). CEA has similar selectivity in well, moderately and poorly differentiated adenocarcinoma (P>0.05). Compared with CEA, the expression of LEA has lower positive rate in non-cancerous tissue (P<0.05). The positive rate of LEA in adenoma is much higher than surrounding non-cancerous mucosa and normal mucosa. In normal mucosa the positive rate of LEA is obviously lower than that of CEA (P<0.05). The expression of LEA and CEA has similar rule except in normal mucosa. In histological diagnosis of colorectal cancer the sensitivity of LEA is 82.9% and the specificity is 48%, while the sensitivity of CEA is 88.6% and the specificity is 35%. Conclusion: The expression of LEA is related to the differentiation degree of colorectal cancer tissue. LEA can be used as an auxiliary index for early diagnosis and a reference for the judgment of the malignancy degree of colorectal carcinoma, thus may be a new tumor marker with applicable clinic value.