Metalloproteinaaseja, niiden valtavaa vaikutusta ei vielä pystytä hallitsemaan lääkkeellisesti.
https://www.dovepress.com/impact-of-semaphorin-expression-on-prognostic-characteristics-in-breas-peer-reviewed-fulltext-article-BCTT
Ramesh Butti, Totakura VS Kumar, Ramakrishna Nimma, Gopal C Kundu
Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Savitribai Phule Pune University, Pune, India
Abstract: Breast cancer is one of the major causes of cancer-related deaths among women worldwide. Aberrant regulation of various growth factors, cytokines, and other proteins and their receptors in cancer cells drives the activation of various oncogenic signaling pathways that lead to cancer progression. Semaphorins are a class of proteins which are differentially expressed in various types of cancer including breast cancer. Earlier, these proteins were known to have a major function in the nerve cell adhesion, migration, and development of the central nervous system. However, their role in the regulation of several aspects of tumor progression has eventually emerged. There are over 30 genes encoding the semaphorins, which are divided into eight subclasses. It has been reported that some members of semaphorin classes are antiangiogenic and antimetastatic in nature, whereas others act as proangiogenic and prometastatic genes. Because of their differential expression and role in angiogenesis and metastasis, semaphorins emerged as one of the important prognostic factors for appraising breast cancer progression.
Keywords: breast cancer, tumor microenvironment, semaphorins, plexins, neuropilins, cancer stem-like cells, prognostic factor, angiogenesis, metastasis, epithelial to mesenchymal transition, vascular endothelial growth factor
- "....The other members of class 3 semaphorins, such as Sema3C and Sema3E, are overexpressed in breast cancer cells and exhibit tumor-promoting function. Zhu et al have shown that siRNA-mediated knockdown of Sema3C in breast cancer cells abolishes cell proliferation and migration.49 Interestingly, the p65-Sema3C fragment that is generated from cleavage of full-length Sema3C by FPPC shows tumor-promoting role. Full-length Sema3C shows inhibitory effect on lymphangiogenesis and metastasis in mice breast tumor xenografts (Figure 2).50 Nonetheless, the metalloprotease ADAMTS1 induces Sema3C cleavage from ECM and converts it to a soluble form, so that it diffuses and promotes tumor cell migration.51 The role of Sema3C in regulation of tumor progression also depends on the type and nature of cancers. For example, Sema3C promotes pancreatic cancer progression through ERK1/2 signaling pathway.52 However, the molecular mechanism by which Sema3C promotes breast cancer progression is unclear.
. (Figure 1).26 Semaphorins also harbor other distinctive protein domains such as basic charged C-terminal domain, thrombospondin repeats, and immunoglobulin (Ig)-like domains. Class 3 semaphorins are characterized by a conserved, basic charged domain at the C-terminal region and these are secreted semaphorins (Figure 1).10 Class 4–7 semaphorins are cell membrane-anchored proteins that are characterized by their distinct structural elements. Thrombospondin repeats are present in case of class 5 semaphorins, whereas a glycophosphatidylinositol anchor is present in class 7 semaphorins (Figure 1). Membrane-anchored semaphorins can be further processed into soluble forms through the proteolytic cleavage at a specific site as in the case of class 4 and 7 semaphorins by ADAMTS1 and furin-like proprotein convertase (FPPC; Figure 1).27,28
Figure 2 Semaphorin signaling in breast cancer.
Notes:
Sema3A interacts with NRP1 receptor to induce PTEN/FOXO 3a-dependent
MelCAM expression, which, in turn, inhibits tumor growth and
angiogenesis. Sema3B binds to NRP1 and induces apoptosis by inhibiting
PI3K/Akt signaling. Full-length Sema3C interacts with NRP2 on the
lymphatic endothelial cells in tumor and suppresses lymphangiogenesis
and metastasis by inhibiting VEGF-C–dependent ERK1/2 and Akt signaling.
Full-length Sema3C undergoes proteolytic cleavage by FPPC to form
p65-Sema3C, which promotes cancer cell survival. Sema4D binds to
plexin-B1 and activates ErbB2, which, in turn, phosphorylates plexin-B1.
Phosphorylated plexin-B1 induces migration by activating RhoA GTPase.
Cleaved p61-Sema3E binds to plexin-D1 to promote metastasis through
ErbB2-dependent MAPK signaling. Sema3E binds to plexin-D1 to inhibit
apoptosis by disrupting the interaction between plexin-D1 and NR4A,
which is known to induce caspase-9–mediated apoptosis. Sema7A interacts
with integrin β1 on the cancer cells to promote invasion. Tumor-derived
Sema7A binds with integrin β1 on the macrophages to promote angiogenesis
by producing CXCL2, CXCL1, and MMP-9.
Abbreviations:
ERK1/2, extracellular signal-regulated kinases1/2; FPPC, furin-like
proprotein convertase; MMP, matrix metalloproteinase; PTEN, phosphatase
and tensin homolog; VEGFR, vascular endothelial growth factor receptor.
