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As an intelligent disease, tumors apply several pathways to evade the immune system. It can use alternative routes to bypass intracellular signaling pathways, such as nuclear factor-κB (NF-κB), Wnt, and mitogen-activated protein (MAP)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). Therefore, these mechanisms lead to therapeutic resistance in cancer. Also, these pathways play important roles in the proliferation, survival, migration, and invasion of cells. In most cancers, these signaling pathways are overactivated, caused by mutation, overexpression, etc. Since numerous molecules share these signaling pathways, the identification of key molecules is crucial to achieve favorable consequences in cancer therapy. One of the key molecules is the mesenchymal-epithelial transition factor (MET; c-Met) and its ligand hepatocyte growth factor (HGF). Another molecule is the epithelial cell adhesion molecule (EpCAM), which its binding is hemophilic. Although both of them are involved in many physiologic processes (especially in embryonic stages), in some cancers, they are overexpressed on epithelial cells. Since they share intracellular pathways, targeting them simultaneously may inhibit substitute pathways that tumor uses to evade the immune system and resistant to therapeutic agents.

Development of engineered non-pathogenic bacteria, capable of expressing anti-cancer proteins under tumor-specific conditions, is an ideal approach for selectively eradicating proliferating cancer cells. Herein, using an engineered hypoxia responding nirB promoter, we developed an engineered Escherichia coli BW25133 strain capable of expressing cardiac peptides and GFP signaling protein under hypoxic condition for spatiotemporal targeting of mice mammary tumors. Following determination of the in vitro cytotoxicity profile of the engineered bacteria, selective accumulation of bacteria in tumor microenvironment was studied 48 h after tail vein injection of 108 cfu bacteria in animals. For in vivo evaluation of antitumoral activities, mice with establishment mammary tumors received 3 consecutive intravenous injections of transformed bacteria with 4-day intervals and alterations in expression of tumor growth, invasion and angiogenesis specific biomarkers (Ki-67, VEGFR, CD31and MMP9 respectively), as well as fold changes in concentration of proinflammatory cytokines were examined at the end of the 24-day study period. Intravenously injected bacteria could selectively accumulate in tumor site and temporally express GFP and cardiac peptides in response to hypoxia, enhancing survival rate of tumor bearing mice, suppressing tumor growth rate and expression of MMP-9, VEGFR2, CD31 and Ki67 biomarkers. Applied engineered bacteria could also significantly reduce concentrations of IL-1β, IL-6, GC-SF, IL-12 and TNF-α proinflammatory cytokines while increasing those of IL-10, IL-17A and INF-γ. Overall, administration of hypoxia-responding E. coli bacteria, carrying cardiac peptide expression construct could effectively suppress tumor growth, angiogenesis, invasion and metastasis and enhance overall survival of mice bearing mammary tumors.

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Mucin-1 (MUC-1) is a transmembrane glycoprotein, which bears many similarities between dogs and humans. Since the existence of animal models is essential to understand the significant factors involved in breast cancer mechanisms, canine mammary tumors (CMTs) could be used as a spontaneously occurring tumor model for human studies. Accordingly, this review assessed the comparison of canine and human MUC-1 based on their diagnostic and therapeutic aspects and showed how comparative oncology approaches could provide insights into translating pre-clinical trials from human to veterinary oncology and vice versa which could benefit both humans and dogs.

Breast cancer research center motamed cancer institute 2 Breast cancer research centaer motamed cancer institute 3 breast cancer research center motamed cancer institute

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BackgroundApplication of genetically modified non-pathogenic bacteria expressing specific anti-tumor proteins under certain conditions specific to tumors is an effective approach for selective targeting of tumors. We developed here, for the first time, a novel spatiotemporal cancer targeted therapy applying engineered E. coli bacteria with capability of expressing cardiac peptides under hypoxic conditions of tumor. MethodE. coli BW25133 was transformed with construction of co-expressing cardiac hormones and GFP. Bacteria bearing constructs were then IV administered in mice bearing tumors and then tumor localization, as well as tumor proliferation, invasion and angiogenesis biomarkers (Ki-67, VEGFR, CD31and MMP9), changes in cytokine profile, suppression of tumor growth and survival were analyzed. ResultsIV Administered bacteria bearing constructs could specifically localize at tumor site and express cardiac peptides under hypoxic conditions. Administration of bacteria significantly enhanced survival rate, suppressed tumor progression and lowered expression levels of MMP-9, VEGFR2, CD31 and Ki67 as potent markers for angiogenesis, tumor proliferation and metastasis. Furthermore, applied bacteria resulted in significant reduction in the expression of IL-1β, IL-6, GC-SF, IL-12 and TNF-α proinflammatory cytokines, whereas increasing IL-10, IL-17A and INF-γ cytokines. ConclusionOverall, administration of E. coli bearing cardiac hormone expression construct could effectively suppress tumor growth, angiogenesis, invasion and metastasis while enhancing survival rate in mice model of breast cancer.