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Page 4 of 25 Torres et al. J Cancer Metastasis Treat 2018;4:4 I http://dx.doi.org/10.20517/2394-4722.2017.49
[43]
Once the tumor cell has escaped the elimination phase, it enters the equilibrium phase . This phases
consists in the destruction of cells expressing tumor antigens in their MHC-1 molecules by T-CD8 +[44] .
Following this, less immunogenic cellular clones will be immunoselected and more aggressive tumor
[43]
cells will grow, directing them to the escape phase . Although evasion of the immune system is
not an isolated event; it also includes an immunological adaptation process. During this process
an immunosuppressed microenvironment comes with recruitment T-reg FOXP3 +[45] and release of
immunomodulatory molecules such as transforming growth factor β (TGFβ), prostaglandin E2 (PGE2),
indoleamin 2,3 dioxygenase (IDO), adenosine, and interleukin-10 (IL 10); also with decreased expression
of co-stimulatory proteins and increased expression of inhibitor molecules such as CTL-4/CD28 and PD-1/
[46]
PD-L1, called checkpoints .
The discovery of these processes has led to research looking for novel immunologic therapies against
[47]
cancer . Most of this therapy approaches have been dedicated to increase active or passive immune
[48]
responses. Others have tried to modify tumor cells to increase recognition by the immune system .
Despite of this, only few immunotherapies have achieved a response strong enough to be clinically
[49]
effective . For these reasons, using bacteria to potentiate response has become a promising strategy.

INCOMING BACTERIOLOGY: ENEMIES OR ALLIES?
Chronic infection with biological agents represents a risk factor associated with cancer, with viral agents
[50]
leading in this field . Bacteria have been associated with cancer because of their effect on cell cycle, and
their capability to evade the immune system and cause immunosuppression through chronic infections [51-53] .
Bacterial infections stimulate phagocyte activity and increase oxidative stress on neighboring cells. The
latter causes the release of reactive oxygen (ROS) and nitrogen (RNS) species such as peroxynitrite
-
-
(ONOO ), reactive hydroxyl group (OH ) and other free radicals that damage cell membranes and DNA,
[54]
affecting enzymatic activity and gene expression . Among DNA alterations mediated by oxidative stress,
the most common includes the formation of 8-oxoguanine and/or 8-2’-desoxyguanosine. These modified
nucleotides are caused by deregulated and repetitive metabolism, and lead to mutagenesis by inhibiting or
[55]
[56]
enabling expression of altered genes . Chronic inflammation is considered carcinogenic by activation
and preservation of nuclear factor ĸB (NF-ĸB) [Figure 2] which modulates gene expression related to cell
[58]
cycle [57,58] , apoptosis [59,60] , proinflammatory cytokines, angiogenic processes , invasion and metastasis [61,62] .
Infectious agents can act directly on the genome of their carrier and promote carcinogenesis by inactivation
of tumor suppressor genes or mitotic stimulation. For example, chronic infections with Helicobacter pylori
(H. pylori) carrying CagA positive virulence factor, causes mutations on p53 protein and adenomatous
polyposis coli (APC) tumor suppressor genes; it can also induce loss of deleted in colorectal carcinoma
[52]
(DCC) gene and microsatellite instability . Cases of infection by Mycobacterium tuberculosis affect tissue
structure, generating a fibrotic scar that will probably increase the risk of carcinogenesis by blocking the
lymphatic flow that decreases activated leucocyte depuration and increases risk for metastatic deposits.
Mycobacterium tuberculosis can also modulate tumor immunity together with the frequent co-infection
with the human immunodeficiency virus (HIV), promoting survival of the bacillus and inhibiting INF-γ
[63]
secretion with increase in TNF-α secretion .

Epidemiologic studies support a relationship between bacteria and cancer. Salmonella tiphy chronic
[64]
carrier state is related to gallbladder cancer , Streptoccocus bovis, found in bacteremia complications and
[53]
infective endocarditis, is related to colorectal tumors , H. pylori, known by its relationship with gastric
[52]
adenocarcinoma, is also related to esophageal cancer , and Chlamydia pneumoniae has been considered as
[51]
an etiological factor in patients with lung cancer .