A screening procedure was used to identify cell fusion (hyphal anastomosis) mutants in the Neurospora crassa single gene deletion library. Mutants with alterations in 24 cell fusion genes required for cell fusion between conidial anastomosis tubes (CATs) were identified and characterized. The cell fusion genes identified included 14 genes that are likely to function in signal transduction pathways needed for cell fusion to occur (mik-1, mek-1, mak-1, nrc-1, mek-2, mak-2, rac-1, pp2A, so/ham-1, ham-2, ham-3, ham-5, ham-9, and mob3). The screening experiments also identified four transcription factors that are required for cell fusion (adv-1, ada-3, rco-1, and snf5). Three genes encoding proteins likely to be involved in the process of vesicular trafficking were also identified as needed for cell fusion during the screening (amph-1, ham-10, pkr1). Three of the genes identified by the screening procedure, ham-6, ham-7, and ham-8, encode proteins that might function in mediating the plasma membrane fusion event. Three of the putative signal transduction proteins, three of the transcription factors, the three putative vesicular trafficking proteins, and the three proteins that might function in mediating cell fusion had not been identified previously as required for cell fusion.The process of cell-to-cell fusion plays a vital role in the life cycles of almost all multicellular organisms. Fertilization, the fusion of an egg and sperm, is a required cell-to-cell fusion event for sexually reproducing organisms. For vertebrates, cell fusion is a critical step in the development of muscle, placenta, and bone and plays an essential role in the formation of multinucleated giant cells in the immune system. Hyphal cell fusion plays an important role in the life cycle of Neurospora crassa and other filamentous fungi (1,6,12,24,38). During the life cycle of the filamentous fungus Neurospora crassa, cell fusions occur during at least three stages (12, 38). During sexual development, fertilization occurs as a protoperithecium (immature female mating structure) generates a trichogyne (long specialized hyphae) that chemotrophically grows toward a conidium (asexual spore) or hypha of the opposite mating type and undergoes cell fusion with it. During the germination of N. crassa conidia, the cells produce short, specialized thin hyphae called conidial anastomosis tubes (CATs), which mediate cell fusion between the germlings and generate an interconnected hyphal network (38,41). This process of cell fusion between conidia allows the cells to share resources and may be critical to the establishment of a colony under some environmental conditions. Cell fusions also occur during the growth of a vegetative N. crassa colony. A few millimeters behind the growing edge of the colony, specialized fusion hyphae are formed as branches from the vegetative hyphae. The fusion hyphae grow toward each other in a directed manner and undergo cell fusion to generate an interconnected hyphal network within the colony (18). Cytoplasm and organelles flow f...
REVIEW BackgroundBreast cancer is one of the most prevalent cancers in women worldwide [1,2] and is the most common cause of cancer deaths in women [2]. The deaths related to breast cancer are not due to the primary tumors, but are due to the metastases to the lungs, brain and bone [3,4]. Therefore, treatment and management to block metastases is an important target for therapy that would improve survival in breast cancer patients.Irregularities in cell adhesion play an important role in cancer progression and metastasis [5]. The Thomsen-Friedenreich antigen (TF-Ag) is the disaccharide, galactose-β1-3N-acetyl galactosamine (Galβ1-3GalNAc) α-O-linked to serine or threonine residues in glycoproteins [6]. It is a tumor-associated antigen, which is covered by other carbohydrate moieties and thus hidden in normal cells, but exposed in cancers such as breast, lung, prostate and bladder [6][7][8][9]. TF-Ag plays a role in cancer cell adhesion and metastasis as a result of interacting with lectins at metastatic sites [10,11]. One particular lectin that interacts with the TF-Ag to establish metastasis is galectin-3. This interaction may provide an explanation for the direct relationship between TF-Ag expression, galectin-3 expression and cancer metastasis and aggression, with patients having elevated galectin-3 levels and tumor cells bearing elevated TF-Ag levels having the most aggressive, metastatic cancers [11,12]. Previous studies proposed that TF-Ag and galectin-3 interaction with galectin-3 mobilization to the endothelial cell surface is involved in the first step of a two-step tumor cell-endothelial cell interaction for tumor adhesion and metastasis [10]. This step is followed by an integrin-mediated orders, please contact: reprints@futuremedicine.com
JAA-F11 is a highly specific mouse monoclonal to the Thomsen-Friedenreich Antigen (TF-Ag) which is an alpha-O-linked disaccharide antigen on the surface of ~80% of human carcinomas, including breast, lung, colon, bladder, ovarian, and prostate cancers, and is cryptic on normal cells. JAA-F11 has potential, when humanized, for cancer immunotherapy for multiple cancer types. Humanization of JAA-F11, was performed utilizing complementarity determining regions grafting on a homology framework. The objective herein is to test the specificity, affinity and biology efficacy of the humanized JAA-F11 (hJAA-F11). Using a 609 target glycan array, 2 hJAA-F11 constructs were shown to have excellent chemical specificity, binding only to TF-Ag alpha-linked structures and not to TF-Ag beta-linked structures. The relative affinity of these hJAA-F11 constructs for TF-Ag was improved over the mouse antibody, while T20 scoring predicted low clinical immunogenicity. The hJAA-F11 constructs produced antibody-dependent cellular cytotoxicity in breast and lung tumor lines shown to express TF-Ag by flow cytometry. Internalization of hJAA-F11 into cancer cells was also shown using a surface binding ELISA and confirmed by immunofluorescence microscopy. Both the naked hJAA-F11 and a maytansine-conjugated antibody (hJAA-F11-DM1) suppressed in vivo tumor progression in a human breast cancer xenograft model in SCID mice. Together, our results support the conclusion that the humanized antibody to the TF-Ag has potential as an adjunct therapy, either directly or as part of an antibody drug conjugate, to treat breast cancer, including triple negative breast cancer which currently has no targeted therapy, as well as lung cancer.
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