Microbiome and Cancer

Dr.K.C.Goutham Reddy
DNB Medical Oncology
Basavatarakam Indo American Cancer hospital
Hyderabad
Science is nothing but collection of the stories of
extraordinarily committed Individuals
Emergence of Microbiota
 Van Leeuwenhoek is a
cloth shopkeeper
 He wanted to see the
quality of the thread
better than what was
possible using the
magnifying lenses of
the time.
 So he invented a
microscope which
could see the thread
better
Discovery of Micro-organisms
 Antonie Van
Leeuwenhock analysed
a plaque between his
own teeth and he
reported in a letter
that he observed little
living creatures called
ANIMALCULES
 This discovery marked
the beginning of a new
science called
MICROBIOLOGY
Germ Theory of disease
 Heinrich Hermann Robert
Koch was a German
physician and
microbiologist he identified
the specific causative
agents of tuberculosis,
cholera, and anthrax
 He proposed four basic
criteria (known as Koch's
postulates) for
demonstrating, in a
scientifically sound manner,
that a disease is caused by
a particular organism.
Role of Bacteria in Health
 Élie Metchnikoff father
of natural immunity.
 Mechnikov developed
a theory that aging.
 Based on this theory,
he drank sour milk
every day in which he
espoused the potential
life-lengthening
properties of lactic
acid bacteria.
Human Microbiome
 In days to come it is been discovered that
there are about 3 x 1013 bacterial cells in
the body comprimising of different
species.
 These microbiota exhibit commensalism
to host cells.
 The number of microbial genes are 100
times more than our genes.
Role of Human Microbiome

Cardiovascular
Metabolism Energy Balance
Functions

Circadian Innate
Inflammation
Rhythm Resistance

Adaptive
Immunity
Metaorganism
 The microbial genome is integral part of
our own genetics.
 We should look upon human body as a
Metaorgnanism composed of large human
host and commensual microorganisms
Cancer as Disease of Metaorganism
 The microbiota affects predisposing
conditions, initiation, progression,
response to therapy, and development of
comorbidities.
 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.
 The New Hall Mark
Thus, cancer should be considered as a
systemic disease of the metaorganism that
modifies and is modified by the
composition of the microbiota and that can
be possibly altered or treated by targeting
the microbiota.
Role of Microbiota
Cause of
Cancer Drugs
Cancer

Drug
Chemotherapy
Metabolism

Immunotherapy
Cause of Cancer
 The role of the microbiota and dysbiosis
(i.e., an alteration of microbiota composition
associated to pathology) in the etiology of
cancer has been inferred based on
epidemiologic studies.
 Dysbiosis or changes in the abundance of
microbial families observed in the patients
may be a consequence rather than a cause of
cancer.
 This concept is now explored as screening in
certain cancers.
Microbiota and cause of Cancer

Helicobactor Pyroli and Stomach Cancer

Colorectal Cancer

Tumour in tissues not directly colonised by the

microbiota

Microbiota and Cancer Predisposing Conditions

and Co morbidity
Helicobactor Pyroli and Cancer
Eradication of H Pyroli may
enhance susceptibility of
Gastroesophageal Reflux and
increased Risk of Gastric Cardia
and esophageal carcinoma

Effect the genomic integrity of

gastric epithelial cells which may
lead to MALTOMA-CAG A
Colorectal Cancer
 Fusobacterium species, anaerobic gram-
negative bacteria that form dental biofilms
and occasionally induce oral pathology,
can reach and colonize the inflamed colon
and have been observed to be enriched in
human colonic adenomas and
adenocarcinomas.
Pathogenesis
 F. nucleatum has been proposed to be
procarcinogenic by recruiting tumor-
promoting myeloid cells, promoting
chemoresistance by modulating
autophagy, inhibiting human natural killer
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.
Fusibacterium as Screening Tool
 FadA gene transcripts are expressed at
significantly higher levels in the colon of
patients with colorectal carcinoma than in
healthy individuals, indicating the
possibility to use FadA as a diagnostic
marker and therapeutic target
Bateriods Fragilis
 B. fragilis, a subclass of the human commensal B.
fragilis. Although enterotoxigenic B. fragilis is normally
present in the intestine at low abundance, it can
become a pathobiont that causes diarrhea, and it has
been associated with inflammatory bowel disease and
colorectal cancer.
 Enterotoxigenic B. fragilis and its toxin stimulate
intestinal epithelial cell proliferation via E-cadherin
degradation and β-catenin activation, induce mucosa
permeabilization, induce STAT3 activation in both
epithelial cells and inflammatory cells, and, in
experimental animals, induce colon carcinogenesis
characterized by expansion of both T regulatory cells
and Th17 cells.
Microbiota Modulation of Cancer
Predisposing Condition
 The gut microbiota modulate energy balance and
metabolism lead to metabolic disease and obesity
which are cancer predisposing conditions.
 Bacteria expressing β-glucuronidases and β-
glucuronides participate in estrogen metabolism,
thus affecting endometrial and breast cancer
through a noninflammatory pathway.
 Microbial β-glucuronidases also metabolize
xenobiotics and transform heterocyclic aromatic
amines from burned meat or environmental
pollutants into genotoxic and procarcinogenic
metabolites.
Microbiota and Drug Metabolism
 The metabolism and pharmacokinetics of
certain anticancer drugs following enteral
(e.g., oral) or parenteral (e.g., intravenous)
administration is affected by the
microbiota
 Absorption and bioavailability of certain
oral drugs is regulated by intestinal host
and bacterial enzymes.
Irinotecan
 The intravenous chemotherapeutic drug
CPT-1151 is transformed by liver and small
intestine tissue carboxylesterases into its
active form, SN-38, that is then detoxified in
the liver by host uridine 5′-disphospho
(UDP)-glucuronosyltransferases into inactive
SN-38-G before being secreted into the gut.
 The inactive SN-38-G is reconverted by
intestinal bacterial β-glucuronidases into
active SN-38 able to provoke intestinal
toxicity and diarrhea.
Clinical Application
 In mice, it has been shown that the
reduction of the number of β-
glucuronidase-positive bacterial species by
antibiotics or the use of bacterial β-
glucuronidase inhibitors reverse the CPT-
11 intestinal toxicity.
Gemcitabine
 Tumor-associated gammaproteobacteria
have been described in mice to inactivate
the drug gemcitabine via bacterial cytidine
 The authors reported the presence of
proteobacteria in a large proportion of
human pancreatic ductal adenocarcinoma,
a tumor type frequently treated with
gemcitabine
Microbiota and Chemotherapy
 Bacteria can directly interact with certain
chemotherapeutic compounds modifying
their chemical structure and altering their
activity.
Bacteria Drug

E Coli Inhibit the Gemcitabine

action of
Parabacteroides Doxurubicin
Distasions
Lactobacillus Cisplatin and
acidohillus promotes Oxaloplatin
Lactobacillus Johnsonii Cylophosphamide
Lactobacillus Murnus mediated
Eterococcus Hirae Immunemediated Cell
Promotes Death
Platinum Analogues and Microbiota
 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
 In microbiota depleted mice, the drug enters
the tumor and forms platinum-DNA adducts
but in the absence of ROS production little
DNA damage is observed.
 Administration of Lactobacillus acidophilus
to antibiotic-treated mice restores cisplatin
antitumor activity
Cylophosphamide
 The mechanism by which CTX kills tumor
cells induces immunogenic cell death that,
together with the translocated bacteria,
induces an antitumor immune response
characterized by the activation of pathogenic
T-helper 17 (pTh17, coexpressing interferon-
γ and IL-17) cells and memory Th1 cells.
 In germ-free mice and in antibiotic-treated
mice, the pTh17 response and the antitumor
effect of CTX treatment are reduced
MICROBIOTA AND
IMMUNOTHERAPY
 Composition of the gut microbiota
modulates the response to
immunotherapy.
Anticancer adoptive T-cell therapy
 The efficacy of anticancer adoptive T-cell
therapy in mice preconditioned with total
body irradiation was shown to require the
presence of the gut microbiota.
 Total body irradiation was shown to induce
mucosa damage that allows the translocation
of bacteria to the mesenteric lymph nodes
activated dendritic cells enabling optimal
expansion and antitumor effect of the
transferred CD8+ T cells.
TLR9 agonist CpG oligonucleotide
 The TLR9 agonist CpG oligonucleotide
(CpG-ODN) induces a strong antitumor
effect when injected intratumorally in tumor-
bearing mice.
 The ability of the tumor-associated myeloid
cells to produce proinflammatory cytokines
in response to CpG-ODN is greatly
diminished in germ-free or antibiotic-treated
mice, preventing the induction of the TNF-
dependent necrosis and of the antitumor
immune response
Anti CTLA blockers and Microbiota
 Anti-CTLA-4 prevents the suppressive
interaction of CTLA-4 with its CD80 and
CD86 ligands, thus enhancing T-cell immune
responses.
 Successful antitumor activity of checkpoint
blockers is often accompanied by severe
toxicity, mostly colitis and hypophysitis.
 The composition of the gut microbiota has
been shown to modulate the efficacy of
anti–CTLA-4 and anti–PD-1/PD-L1 therapy
both in experimental animal and clinical
studies.
Anti PD1 /PD L1 and Microbiota
 Successful antitumor activity of
checkpoint blockers associated with
pneumonitis.
 Gut Bacteria composition modulate the
efficacy of Anti PD L1 molecules
Efficacy of Anti PDL1
 Cancer patients with a healthier, highly diverse
microbiota and harboring in their intestine
certain bacterial species appear to be able to
mount a more robust antitumor immune
response at baseline that can be enhanced by the
anti–PD-1 treatment with increased probability of
a favorable clinical response.
 However, antibiotics treatment within a couple of
months of the initiation of anti–PD-1 therapy
disrupts the microbiota balance and hampers the
response to therapy reducing in half the
progression-free survival of the patients.
What Next?
 Culture primary clinical bacterial isolates
that will allow the identification of new
species and strains and their use in
mechanistic studies.
 How to target the microbiota to increase
the number of patients that can benefit
from the therapy