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Page 2 of 25 Torres et al. J Cancer Metastasis Treat 2018;4:4 I http://dx.doi.org/10.20517/2394-4722.2017.49

INTRODUCTION
At present, cancer has one of the highest morbidity and mortality rates worldwide, nationwide and
statewide [1,2] . It comes from the growth of uncontrolled and invasive malignant cells with DNA
[3]
mutations capable of producing multiple diseases . Most of these malignant neoplasms have the same
etiopathogenesis. However, the diversity on the anatomic location, histologic origin, immunologic
[4]
characteristics and intrinsic spreading capacity (intertumoral heterogeneity) , and different genomic
[5]
alterations inside the same tumor (intratumoral heterogeneity) have shown the need for specific
biomarkers and individualized therapy to improve patient prognosis.

Currently, conventional therapy such as surgery, chemotherapy, radiotherapy, or mixed therapy have
[6,7]
increased survival rates worldwide against cancer in different subtypes . However, these practices produce
[8]
many adverse effects and have shown a limited tumor penetrance . The role of the immune system has
been studied in order to find a therapeutic approach with equivalent therapeutic potency and controlled
[9]
damage to healthy tissue; which gave rise to immunotherapy as a novel treatment .
Nowadays, many of these therapies are being used in clinical settings, including the checkpoint inhibitors
monoclonal antibodies anti cytotoxic T-Lymphocyte associated protein 4 (CTL-4) and programmed death
[10]
protein 1 (PD1). They have been shown to increase survival in patients with metastatic melanoma
but their mechanism of action decreases immunotolerance with systemic administration. The latter may
[11]
cause autoimmune adverse effects, limiting its use only for specific patients . In the last few decades,
experimental studies and clinical trials have been aimed to assess bacteria therapeutic functions [12-15] .
Bacteria selective replication within the tumor microenvironment gives them antitumor effect and
minimizes systemic adverse effects. On the other hand, expression of multiple ligands, immunostimulants,
cytokines and tumor antigens can be achieved through gene manipulation to increase the therapeutic effect
against specific tumors.

Cancer causes many physical and psychological effects to the patients and their families, but it also
increases state expenditures. For these reasons, evaluation of these novel therapies in clinical settings
has great importance. This review brings the basic science principles in genetics, immunology, and
microbiology that gave rise to this therapeutic approach, in addition to its latest experimental and clinical
advances.

THE BEGINNING: GENETIC AND IMMUNOLOGIC BASIS IN CARCINOGENESIS
Carcinogenesis begins as a result of multiple genomic alterations within a cell. They come from a prolonged
[16]
[18]
[17]
exposure to different mutagens , adverse epigenetic factors , as well as chronic infections . These
[19]
[20]
alterations increase proliferation and affect cell cycle through gene functioning , in proto oncogenes
[21]
[22]
and tumor suppressor genes , causing different mutations . They ultimately modify the cell physiology
making a mutated cell capable to generate its own mitogenic signals, resist against growth inhibitory
[3]
signals, and acquires its own blood vessels. In advanced stages it can even invade and metastasize .
The role of the immune system in tumor surveillance comes from the response to multiple oncogenic
viruses and other infecting agents that can induce a chronic inflammatory environment leading to
carcinogenesis [23,24] . Identification of tumor-specific antigens (TSA) induces an immune response on
[24]
carcinogenesis at an early stage . Tumor cells generate multiple modified surface proteins, decreasing
immunologic tolerance as carcinogenesis progresses, and many TSA are expressed . The immune system
[25]
can recognize and eliminate abnormal cells, in a continuous and bidirectional pathway between innate
[26]
[27]
and adaptive immunity, which is called “Immunosurveillance” . Natural killer (NK) cells and cytotoxic