- The human microbiome plays an important role in cancer development through various mechanisms such as inducing chronic inflammation, causing DNA damage, modulating host immunity, and activating cell proliferation pathways. Certain bacteria like Helicobacter pylori and Fusobacterium nucleatum have been shown to directly contribute to cancer initiation in tissues like the stomach and colon. The composition of the gut microbiome can also affect response to cancer therapies by interacting with chemotherapy drugs and priming immune cells.

1. Microbiome and Cancer

2. • All the epithelial barriers of our body harbor
different densities of commensal microorganisms
• The microbiota—including eubacteria, archaea,
protists, fungi, and viruses mostly exhibits
commensalism with the host.
• Approximately 3 × 1013 bacterial cells present in
human body, particularly abundant in lower
intestine.

3. • The number of microbial genes in the microbiota is
more than 100 times higher than that of human genes.
• mutualism between the human and the microbial cells
modulates most physiologic functions.
• Unlike our own genome that is fixed, the microbiota
metagenome can respond to environmental stimuli
with rapid alteration of different strains, exchange of
genetic elements, and mutations.

4. • Factors affecting microbiota :
– host genetics
– colonization at the time of birth
– type of birth delivery
– individual lifestyle
– diseases
– exposure to antibiotics

5. • Sequencing of one or more variable regions of the
gene-encoding 16S rRNA is the most widely used
method for the identification of bacterial and archaeal
taxa.
• Identification of fungi relies on sequencing the internal
transcribed spacer region between the 18S and 28S
rRNAs.
• Shotgun sequencing of the whole microbial
metagenome allows a better taxonomic classification
at species level

6. • Microbiota also plays an important role in the
cancer process affecting predisposing conditions,
initiation, progression, response to therapy.
• The composition of the microbiota and
particularly of the very abundant gut microbiota
modulates the tumor microenvironment and
affects tumor growth both at the level of the
epithelial barriers and systemically

7. Bacteria as Cause of cancer
• mostly limited to cancers of the GI tract and of
the lung and based on the analysis of oral, fecal,
and tissue samples.
• Helicobacter pylori is the only bacterial species
recognized as a group 1 human carcinogen.
• Dysbiosis or changes in the abundance of
microbial families observed in the patients may
be a consequence rather than a cause of cancer

8. • The microorganisms that were involved in cancer
initiation may no longer be present when the
patients are studied.
• Except for H. pylori, none of the bacteria
associated with human cancer has been formally
proven to be a human carcinogen
• However, mechanistic studies in mice are starting
to provide evidence of a direct role in colon
carcinogenesis for several bacterial species

11. • Although these mechanisms have been
studied primarily for intestinal microbiota,
microbes colonizing other epithelial barriers
(e.g., the oral cavity and the skin) are also
expected to mediate both local and systemic
effects.

12. H Pylori and Ca Stomach
• H. pylori is epidemiologically associated with
noncardia gastric carcinoma and lymphoma.
• In most individuals it causes only gastritis but
in a few patients, it causes serious pathologic
lesions including atrophy, metaplasia, and
cancer

13. • Two toxin-encoding genes cytotoxinassociated
gene A (cagA) and vacuolating gene (vacA) are
present in virulent and carcinogenic strains of
H. Pylori.
• H. pylori directly can affect genetic integrity of
gastric epithelial cells by inducing DNA
damage.

14. • Development of gastric cancer requires a
multidecade exposure to the bacterium
associated with:
– inflammatory response inducing epithelium injury
– atrophy
– reduction in acid secretory functions
– metaplasia.

15. • Atrophic gastritis results in dysbiosis and
gastric colonization with cancer-provoking
bacterial species of oropharyngeal or
intestinal origin.
• Eradication of H. pylori may enhance
susceptibility to asthma and obesity as well as
gastroesophageal reflux with increased risk of
gastric cardia and esophageal carcinoma.

16. • H pylori causes intestinal metaplasia leading
to intestinal type of gastric adenocarcinoma.
• The intestinal type of sporadic gastric
adenocarcinoma has a hallmark progression
from normal gastric epithelium, to chronic
atrophic gastritis (typically due to Helicobacter
pylori infection) to intestinal metaplasia to
dysplasia

18. Microbiome and Colorectal Cancer
• Interaction between microbiota and host is
particularly evident in the lower
gastrointestinal tract harboring the largest
number of bacteria.
• Fusobacterium – normally form dental
biofilms commonly found in colonic adenomas
and adenocarcinomas.

19. • F. nucleatum has been proposed to be
procarcinogenic:
– by recruiting tumor-promoting myeloid cells
– promoting chemo resistance by modulating
autophagy
– inhibiting NK and T-cell activity via binding of its Fap2
protein to the TIGIT inhibitory receptor and activating
β- catenin/Wnt signaling in epithelial cells by
association of its FadA adhesin to E-cadherin

20. • FadA gene transcripts are expressed at
significantly higher levels in the colon of
patients with colorectal carcinoma
• thus can be used as a diagnostic marker and
therapeutic target

21. • Fusobacteria biofilms produce the polyamine
metabolite N1,N12-diacetylspermine.
– Enhance epithelial proliferation
– diminish E-cadherin expression
– activate STAT3 and interleukin (IL)-6.

22. Genotoxic Effects
• Toxins injectedvia type 3 secretion :
– Cell toxicity via apoptosis
– Repression of proton pump expression
• Microbial metabolites :
– Products of protien – hydrogen sulphide, cresol
– Products of bile degradation
– Breakdown of liver detoxified xenobiotics

23. • Genomic instability :
– Damages P53, MSH2, MLH 1
• DNA damaging toxins :
– Colibactin – E.coli - disrupts SUMOylation of p53 and
leads to production of proinflammatory and growth
factors with tumor-promoting ability.
– Cytolethal distending toxins ( CDTs) – E.coli,
S.eneterica, C. jejuni

24. • Translocation through barrier causing
recruitment of myeloid cells
• Causes activation of ROS resulting in DNA
damage

25. Activation of Cell proliferation
• Fad A – Fusobacterium
• Cag A – H. Pylori
• BFT – Bacteroids toxin
• Avirulence protien A – S enterica
• Cause detachment of beta catenin from E
cadherin and cause activation of beta catenin
pathway

26. • H pylori and S enterica lead to PI3K/AKT and
MAPK/ERK pathway activation.

27. Modulation of host
immunity
• IL 22 and IL 6 – promote colon cancer via
activation of STAT 3
• IL-18/IL-22 axis plays a particularly important
role in maintaining mucosal homeostasis.

28. Inflammasomes (NLRP3 and/or NLRP6)
↓
activated by bacterial derived small chain fatty
acids (SCFAs) via GPR43 and GPR109a
receptors.
↓
epithelial cell production of pro-IL-18 that is
cleaved into active IL-18

29. IL-18 then blocks macrophage production of the
soluble IL-22 antagonist IL-22BP
↓
increased production and bioavailability of IL-22
↓
IL-22 induces STAT3 phosphorylation in epithelial
cells:
– promoting proliferation,
– secretion of antibacterial peptides
– in a positive feedback loop, enhances production of IL-
18.

30. Immunosupressive Mechanisms
• F. nucleatum promotes accumulation of
immunosuppressive myeloid cells
• produces the Fap2 protein
• activates the inhibitory receptor TIGIT on NK and
T-cells.
• SCFAs induce regulatory T (Treg) cells that inhibit
local immune response

32. • Limited data on carcinogenic potential outside
GIT
• possible contribution to cancers of the skin,
the oropharyngeal cavity, the lung, and the
urogenital tract need to be better investigated

33. • the role of microorganisms other than bacteria and viruses
on carcinogenesis remains to be better defined.
• Fungal infection with production of the carcinogenic
acetaldehyde in patients with autoimmune
polyendocrinopathy-candidiasis ectodermal dystrophy
• leads to mutations in the AIRE gene has been proposed to
play a role in the oral and esophageal cancer observed in
these patients.
• Additionally, other members of our microbiota could also
contribute to cancer including protists and helminths.

34. Tumors in other tissues
• microbiota can also affect the development of tumors in
sterile tissues that are not in direct contact with the
bacteria.
• modulate cancer-predisposing conditions such as metabolic
disease and obesity.
• β-glucuronidases and β-glucuronides participate in
estrogen metabolism.
• affect endometrial and breast cancer through a non
inflammatory pathway.

35. Bacteria as Cancer Drugs
• William Coley observed that acute infections may
be followed by tumor regression.
• In a number of patients with soft tissue sarcoma
he used “Coley’s toxins,” a combination of
Streptococcus pyogenes and gram-negative
Bacillus prodigiosus.
• local treatment with BCG, an attenuated
Mycobacterium bovis strain, is still a widely used
therapy for superficial bladder carcinoma

36. • Large tumors contain hypoxic and necrotic areas with limited tumor
cell proliferation that are poorly accessible to drugs
• relatively resistant to chemotherapy or radiation-induced DNA
damage.
• Obligate anaerobic bacteria such as Clostridium spp. can be
delivered as spores
• germinate and proliferate, mediating an antitumor effect when
they reach the hypoxic tumor tissues

37. • Small tumors or metastases are usually well
oxygenated
• susceptible to antitumor effect of facultative
anaerobes (i.e., Salmonella and Escherichia
genera).
• can be used as vector to deliver toxins, cytokines,
antigens, antibodies, and antitumor genes to the
tumor.

39. • directly interact with certain chemotherapeutic
compounds modifying their chemical structure and
altering their activity.
• Intratumor inoculation of E. coli in tumor-bearing mice
confirmed its ability to inhibit gemcitabine and to
enhance CB1954 antitumor activity in vivo
• detailed mechanistic studies in vivo of the ability of the
microbiota modulate chemotherapy efficacy have only
been reported for platinum compounds and
cyclophosphamide (CTX).

40. • The gut microbiota primes tumor-infiltrating
myeloid cells to produce, via NADPH oxidase 2
(NOX2), reactive oxygen species (ROS) that are
required for oxaliplatin-induced DNA damage.
• In absence of microbiota, the drug enters the
tumor and forms platinum-DNA adducts but in
the absence of ROS production little DNA
damage is observed

41. • administration of probiotics containing L. acidophilus
to patients treated with radiotherapy and cisplatin
improves therapy-induced intestinal damage.
• Cyclophosphamide allows transmucosal translocation
into the mesenteric lymph nodes of gram-positive gut
bacteria.
• induces an antitumor immune response by the
activation of pathogenic T-helper 17 (pTh17,
coexpressing interferon-γ and IL-17) cells and memory
Th1 cells.

42. Bacteria and Immunotherapy
• The efficacy of anticancer adoptive T-cell therapy was reduced in
mice treated with antibiotics or in which the activity of the TLR4-
agonist lipopolysaccharide (LPS) was prevented
• The TLR9 agonist CpG oligonucleotide (CpG-ODN) induces a strong
antitumor effect when injected intratumorally :
– TNF-dependent hemorrhagic necrosis
– antigen-presenting dendritic cells migrate to the tumor-draining lymph
nodes
– Myeloid cells repolarised to inflammatory state within tumor

44. • Immunotherapy with anti–cytotoxic T-
lymphocyte antigen 4 (anti-CTLA-4)
• Induces mucosal damage and translocation of
Burkholderiales and Bacteroidales
• as an adjuvant for antitumor immunity and is
required for positive response to therapy.

45. • antitumor effect of anti–PD-1/PD-L1 therapy
requires preexisting antitumor immunity that
is increased with Bifidobacterium spp.

46. • Thus therapeutically targeting the microbiota
composition may provide new tools for cancer
prevention and treatment and for improving
therapy efficacy.
• The biggest hurdle is still unidentified taxa of
bacteria and the corresponding genetic levels
at which they act.

47. • Thank You