FEATURES engineering methods modify the genetic makeup and sequences of microorganisms.10
Specified Microbial Therapeutic Against Cancer Regardless of their species, all microbial anti-cancer mechanisms can be classified into three categories: direct antitumor mechanism, vasculature destruction, and immune activation. Related treatments can also be enhanced by genetic engineering.
Direct Antitumor Mechanisms Microbes can eliminate tumor tissues by infecting and killing host cells through virulent mechanisms that often lead to cell lysis, the breaking of cell membranes. Some microbes infect tumor cells internally, while many others attack extracellularly. For instance, toxin-bearing microbes produce peptides and virulent elements that can damage tumor tissues and suppress vital functions like immune systems, which is more effective than chemotherapy, as the latter targets all tissues and can cause fatal side effects.11 Microbes can be engineered to transform molecules with little pharmacological activity into toxins or active chemotherapy reactants within target tissues.12 Notably, microbes can also embed radioisotopes-coupled antibodies into their membranes to deliver lethal radiation to tumors.13
Attacks on Vascular Structures Many scholarships have demonstrated that cancerous tumors rely on vasculature, namely blood vessels, to provide oxygen and nutrients for their high metabolism.14 Current chemotherapies, although effective at inhibiting the growth of new blood vessels, are impotent against treating existing vessels that support tumor growths. However, through genetic expressions that allow the development of specific pathway-binding protein structures, microbes can not only suppress tissue growth with higher success rate than traditional treatments but also trigger apoptosis (programmed cell death) in malignant and blood vessel cells.15,16,17 The destruction of harmful vasculature would facilitate immune cells’ targeting on cancer cells and support therapeutic bacterial infections.
Immune Activation Tumors have developed mechanisms that allow them to inhibit and suppress immune cells within tumors.18 However, through both genetic engineered and intrinsic properties, microbes emerge as a useful tool to activate immune systems and attract immune cells. For instance, through infecting tumors, microbes can trigger inflammatory responses of the host’s innate immune system to destroy both cancerous tissues and related vasculatures.19 Specifically, microbes can be engineered to produce cytokine proteins to attract immune cells like macrophages (cells that can filter through tumor membranes, infuse therapeutic microbes, and trigger antitumor inflammations)20 and neutrophils (white blood cell that can stimulate non-specific inflammation).21 Additionally, microbial vaccines can deliver tumortargeting antigens like tumor necrosis factor alpha (TNF-�) to activate adaptive immune responses independent of tumor’s infection status, which allow the implementation of multifaceted attacks.22 Eventually, by inducing immune memory, microbes could help to establish a surveillance system that identifies and removes metastatic cells before they create further dysregulation.23
Concerns One risk of applying microbe-based therapeutics is induced septic shock—a body-wide bacterial infection. When a microbial vaccine activates immune systems, some bacterias might be lysed during the release process of macrophages and excrete toxins that can lead to fatal septic shock. Thus, it is essential for future treatments to minimize that risk. A potential solution is to engineer phage to delete genes corresponding to lysing. Another concern surrounds immune system clearance, which can rapidly clear therapeutic phages and significantly reduce their efficacy. One potential solution is couple directed evolution that can increase phages’ lifetime with genetic engineering that boosts their immunity against the hosts’ immune system.24 REFERENCES
Spring 2022 | PENNSCIENCE JOURNAL 15
