Mechanobiological Response and Network Formation in Central Nervous Development / 医用生物力学

In the process of central nervous system (CNS) development and maturation, the biomechanical factors have not been highly valued for a long time. In recent years, a large number of studies have shown that mechanical environment strongly affects the migration, differentiation and maturation of nerve cells, as well as the cell-cell interactions. Mechanical factors play an important role in realization of the structure and function of the brain and spinal cord. This review briefly summarized the role of biomechanics in CNS perception, path-finding, regulation and network shaping during CNS development. The effects of static and dynamic mechanics on mechanobiological response of nerve cells were also introduced, hoping to provide some ideas for CNS reconstruction and repair in future.

Cancer cell-cell interaction: Notch-1 signaling pathway and its regulation mechanisms / 医用生物力学

Notch-1 signaling pathway is responsible for cell differentiation, development, proliferation and apoptosis. Recent studies show that Notch-1 signaling pathway is also involved in cancer progression, including cell invasion, motility and cancer metastasis. Activation of Notch-1 signaling pathway can directly or indirectly induce cell proliferation and migration. In tumor cells, activation of Notch-1 facilitates epithelial-mesenchymal transition (EMT), keeps its mesenchyme characteristics and induces cell adhesion. Notch-1 signaling pathway also cross-talks with other pathways to regulate cell fate, such as PI3K/Akt, NF-κB pathways. The evidence shows that aberrant Notch-1 activation has been found in different solid tumors, which participates in regulating tumor metastasis. In this review, the Notch structure and function, Notch-1 signal and tumorigenesis, tumor metastasis via Notch-1 signaling, and Notch-1 signaling targeted-therapy were comprehensively summarized. To clarify the roles of Notch-1 signal pathway in tumor metastasis and its regulatory mechanisms as well as the current treatment strategies for Notch-1 signal pathway will provide references for studies on pathomechanism and clinical treatment of cancers.

Permanent Genotypic and Phenotypic Change of Prostate Cancer Cell Line LNCaP through Cellular Interactions with Prostate or Bone Fibroblasts in vitro or in vivo / 대한암학회지

PURPOSE: Cell-cell interactions determine normal prostate development and subsequent neoplastic transfor mation. The progression of prostate cancer from androgen-dependent to androgen-independent states involves multiple steps of genetic changes mediated by tumor-microenvironment interactions. To understand the epigenetic factors that lead to progression, we studied if 1) androgen-dependent and non-metastatic LNCaP may interact with prostate or bone fibroblasts under microgravity-simulated conditions in vitro. 2) LNCaP may interact with prostate fibroblasts in vivo, and acquire androgen-independence and metastatic potential. MATERIALS AND METHODS: The LNCaP sublines were generated as follows. 1) LNCaP cells were grown in vitro either alone or with prostate or bone fibroblasts under microgravity-simulated conditions. 2) LNCaP cells were grown in vivo as chimeric tumors with prostate fibroblasts. The LNCaP sublines were characterized by studies of chromosomal analysis, comparative genomic hybridization and, in vivo tumorigenicity and metastatic potential. RESULTS: In comparison to the parental LNCaP cells, the LNCaP sublines underwent permanent genotypic and phenotypic changes manifested in androgen-independence and metastatic potential. CONCLUSION: These results emphasize the importance of cell-cell interaction as a critical determinant that could "induce" or "select" progenies favoring enhanced prostate cancer growth and progression. This concept favors the development of toxic gene therapy targeting both prostate cancer epithelium and supporting bone stroma for an effective eradication and prevention of prostate cancer bone metastasis.

3-Dimensional Culture of Prostate Organoid under Microgravity-Simulated Growth Conditions: Cell-Cell Interactions Favoring Cancer Growth and Progression / 대한비뇨기과학회지

PURPOSE: Three-dimensional(3-D) organization is critical for both the normal development and, tumor growth and progression. Cell-cell and cell-matrix interactions determine normal prostate development and its subsequent neoplastic transformation. To understand the epigenetic factors that lead to cell transformation, a 3-D human prostate cell culture was established with prostate epithelial cells grown in a rotating-wall vessel(RWV) under microgravity-simulated conditions with either alone or with prostate or bone stromal cells. We tested the hypothesis of whether phenotypic and genotypic alterations of LNCaP cells may be achived when grown as 3-D organoids. MATERIALS AND METHODS: LNCaP cells were seeded in RWV alone and with either human prostate or bone fibroblasts. After period of 2 months, RWV1, 2, and 3 cell lines were established from the prostate organoids and were characterized. RESULTS: While LNCaP cells injected orthotopically failed to form tumors in castrated mouse, RWV-derived cell lines formed PSA-producing tumors and metastasized to lymph node, bone, lung and liver, which stained positively by PSA antibody. RWV cells grew faster than parental LNCaP, especially in sex hormone-free conditions. Unlike parental LNCaP cells which respond positively to androgen and estrogen-induced growth and PSA expression, RWV cells are insensitive to sex steroid-induced growth, but remain sensitive to androgen for induction of PSA expression. Comparative genomic hybridization(CGH) results demonstrated that RWV cell lines have different chromosomal gain and loss each other as compared to those of LNCaP. CONCLUSIONS: Cell-cell and cell-matrix interactions of androgen-dependent and non-metastatic LNCaP cultured alone or with either prostate or bone fibroblasts in 3-D culture under microgravity-simulated conditions resulted in induction of androgen- independent and metastatic LNCaP sublines, RWV cell lines, meaning androgen- independent progression. Phenotype and genotype of RWV cell lines are definitely dissimilar to those of parental LNCaP. 3-D culture of prostatic epithelial cells under microgravity-simulated conditions could be novel approach to the study of normal development and cancer of prostate as an ideal in vitro model and, will be further exploited.

Derivation of Androgen-Independent LNCaP Sublines from Cell-Cell Interactions of LNCaP and Human Prostate Fibroblasts in vivo / 대한비뇨기과학회지

PURPOSE: A cell-cell interaction in which in vivo inoculation of androgen-dependent, non-tumorigenic LNCaP and human bone fibroblast resulted in derivation of androgen-independent and metastatic LNCaP subline(C4-2) in castrated hosts. The purpose of this study is to evaluate if human prostate fibroblasts when grown together with LNCaP may promote androgen-independent growth and enhance metastatic potential. MATERIALS AND METHODS: LNCaP cells and human prostate fibroblasts derived either from peripheral or transition zone co-inoculated in athymic mice for 8 weeks, and then mice were castrated. The chimeric tumors were maintained for additional 4 weeks. The LNCaP sublines, designated P4 and T4, were established and characterized. These sublines were co-inoculated again in castrated mice with human prostate fibroblasts for 8-12 weeks. And then second generation LNCaP sublines, P4-2 and T4-2, were established and also characterized. RESULTS: Marked cytogenetic alterations were observed in P4-2, P4, T4-2 and T4 LNCaP sublines in comparison to parental LNCaP. Although LNCaP cells injected orthotopically did not form tumors in castrated hosts, LNCaP sublines formed PSA-producing tumors and had metastatic potentials to lymph node, lung, liver and bone. These P and T sublines had androgen-independent growth characteristics and metastatic potential. CONCLUSIONS: Cell-cell interactions between prostatic epithelium and their surrounding fibroblasts could contribute to androgen-independent characteristics and enhanced metastatic potential of localized prostate cancer in vivo.