Chronic

Inflammation’s
Transformation to
Cancer:
Done by : Maryam Hamed Muhsen
Almashhad University of Medical Science
Department of clinical chemistry
Chronic Inflammation’s
Transformation to Cancer
• Cancer is the main leading cause of most deaths
worldwide nowadays . The connecting relation
between cancer and inflammation was observed
for the first time in the 19th century by Rudolf
Virchow (a German scientist from Wurzburg), who
founded the possible indication that
inflammation may play a vital part in tumor
progression and development. It was mentioned
that “lymphoreticular infiltrate” showed the
development of tumor cell progression at the
site of chronic inflammation
Chronic Inflammation’s
Transformation to Cancer
• The body’s defense mechanism starts working
against a particular internal cell or tissue
damage that is caused by a foreign body (such
as an irritant, pathogens, or any injury). The
body’s WBCs launch a biological response to
invade that pathogen as a process of healing.
This involves the release of chemicals that
trigger the immune system, releases antibodies
and proteins, and increases the supply of blood
flow to damaged and injured areas. It usually
lasts for hours or days in case of certain
inflammation (acute). Over a prolonged period,
chronic inflammation results in DNA damage and
may give a home to cancer development such as
Chronic Inflammation’s
Transformation to Cancer
• Inflammation associated with cancer is imposed
to fast emergence to resist drugs, showing an
attractive targeting strategy to achieve
prevention, fast recovery, treatment, and
therapy of cancer . The infection that triggers
the chronic inflammation increases the chances
of cancer risk during injury and progression of
infection (such as helicobacter pylori for
hepatocellular carcinoma, mucosal lymphoma and
gastric carcinoma, hepatitis virus for liver
and cervical cancer, and other inflammatory
bowel diseases aligned with colorectal cancer).
Chronic inflammation involves various steps in
cancer progression such as tumorigenesis,
Inflammatory Factors Involved
in Cancer Transformation
• 1. Macrophages and Denticles Cells
Macrophages contain antigen-presenting cells,
immunomodulators, and phagocytosis that play a
vital role in the initiation and maintenance of
inflammatory functions . Macrophages that
infiltrate the tumor parenchyma have an M1
phenotype and M2 phenotype present in the tumor
microenvironment
2. Proinflammatory Cytokinesis
• Inflammatory chemokines and the cytokines that
are produced by tumor-associated leukocytes and
platelets, participate directly in the
progression of malignant cancer. The most basic
physiological difference between normal and
tumor tissue is that many chemokines and
cytokines are induced by hypoxia such as TNF-α,
InterLeukin 6, and InterLeukin-1 α and β. They
are signaled through type 1 cytokines receptors
(CCR1) and are the immune-regulatory
cytokinesis that favors inflammation.
Inflammatory responses are resolute by the net
balance between the anti-inflammatory cytokines
3. Tumor Necrosis Factor α
• They are also involved in endogenous tumor
promotion as they stimulate the metastasis of
cancerous cells. In human cancer, Tumor
Necrosis Factor can be found in stroma and
malignant cells, lungs, breast, prostate,
bladder, and colorectal cancer . In a review,
it was found that by up-regulating the levels
of prion protein (PrP), TNF-α can contribute to
malignant cancer . TNF α promotes the formation
of inflammatory cytokines and stimulates the
permeability of endothelial cells.
4. Interleukin
• IL-6 plays a vital part in inflammatory
responses as it is a pleiotropic cytokine. They
are mainly secreted by monocytes. The secretion
of InterLeukin 6 by immune cells is an
indication of severe infection or major
cell/tissue injuries . Their pro-oncogenic
effect has been demonstrated in different types
of carcinomas including colorectal, breast, and
lung. IL-6, along with the proteins of the STAT
family, helps to regulate carcinogenic
processes, the inhibition of apoptotic
processes, and the release of ROS and RNS.
Inflammatory Signaling
Pathways
• 1. Intrinsic Pathway
• An intrinsic pathway connects inflammation and
cancer genes, genetic changes, or an event that
causes neoplasia. They can be accountable for
the development of an environment that favors
inflammation. In intrinsic pathways, oncogenes,
genetic events along with neoplasia
Inflammatory Signaling
Pathways
• Extrinsic pathways in which chronic
inflammation caused by injury, infection, and
irritants extensively increase the chance of
cancer development. These two pathways converge
to activate transcription factors, which
results to bring the formation of inflammatory
mediators and activate different leukocytes,
which gives rise to cancer-related inflammatory
microenvironments
Inflammatory Signaling
Pathways
• NF-kB has been recognized in gastrointestinal
malignancies such as; hepatocellular and
colorectal carcinoma. Nuclear factor kappa B
consists of 5 ReL proteins family; ReLA, C-ReL,
ReLB, P50/105, and P52/100, among all these ReL
family proteins only ReLA contains carboxy-
terminal transactivation domain necessary for
transcriptional activation . The autocrine
expression of interleukin 1 alpha and beta in
the SUM-149 cell line involve NF-kB activation
i.e., necessary for the growth and
proliferation . IL-6 and IL-8 inflammatory
cytokines are highly secreted during
JAK/STAT Pathway
• The STAT protein determines whether a
particular immune response in the tumor
microenvironment should be promoted or
inhibited. There are seven major STAT family
protein members that are encoded by seven
different genes: STAT (1, 2, 3, 4, 5A, and 5B)
and STAT6. STAT3 has a role in both extrinsic
and intrinsic pathways linked to cancer. STAT
is activated in malignant cells and has the
capability to induce a large number of genes
necessary for inflammation. STAT3 and STAT5 are
activated proteins, which increase tumor cell
proliferation, invasion, and survival. STAT3
plays a dual part in tumor inflammation. It
COX Pathway
• Cyclooxygenase-2 (COX) is the key enzyme in
eicosanoid biosynthesis, several cancers in humans
display upraised levels of prostaglandin (PG) due
to the upregulation of COX-2. Approximately 40% of
overexpressed COX-2 cases have been found in human
breast cancer and pre-invasive ductal carcinoma
(in situ lesions) . The transgenic COX-2
overexpression operates the formation of mammary
tumors and, in reverse elimination of COX-2,
reduces tumor formation in rodent models,
especially for breast, skin, and intestinal
cancers . The COX enzyme family consists of two
members: COX-1 and COX-2 (PG endoperoxide synthase
1 and 2). The upregulation of COX-1 is evoked by
various stimuli such as oncogenes, cytokines (IL-1
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