The tumor microenvironment consists of the cells and molecules surrounding a tumor that interact with and influence tumor growth. It includes blood vessels, immune cells, fibroblasts and the extracellular matrix. The microenvironment experiences metabolic changes like hypoxia and nutrient deprivation that suppress the immune response and promote tumor growth. It also experiences a "cytokine rush" of inflammatory signaling molecules released by tumor and immune cells that further drives inflammation and immune suppression. Key signaling pathways in the microenvironment like TGF-β, NF-κB, JAK-STAT regulate processes like inflammation, cell survival, and stem cell renewal that impact tumor progression. Chronic inflammation and these signaling cascades also facilitate tumor angiogenesis, metastasis, and proliferation at distant sites.

1. TUMOR
MICROENVIRONMENT
Dr. Naila Malkani
Department of Zoology
GC University, Lahore

2. DEFINITION
The tumor microenvironment is the
environment around a tumor, including the
surrounding blood vessels, immune cells,
fibroblasts, signaling molecules and the
extracellular matrix. The tumor and the
surrounding microenvironment are closely
related and interact constantly.

5. Metabolic Changes
• Hypoxic and nutrient deprived supporting suppressed
immune response providing favourable environment for
tumor growth.
• Tumor cell metabolism utilises glucose and glutamine more
efficiently than normal cells which helps tumor growth.
• Excessive utilisation of glucose by growing tumor cells
deprive TME of glucose and a competition between tumor
and T cells.
• Increased glycolysis in tumor cells results into lactate
accumulation in TME making it acidic.
• The increased extracellular glutamine levels also make tumor
cell more aggressive, invasive and with lesser survival period
for patients.

6. Cytokine Rush
• Cytokines rush is the phenomenon characterised by
increased production of cytokines leading to elevated
inflammatory response.
• It can occur in tumor cells due to several underlying factors
as well as with immune based therapeutics.
• Many pro-inflammatory chemokines which are released in
response to infection will recruit cells of immune system like
lymphocytes, macrophages and neutrophils to the site and
increase inflammation and immune suppression.
• Alongwith chemokines, interleukins, tumor necrosis factors
and interferon-gamma are rushed to the site to release
cytokines.
• These excessive cytokines which initially affect the TME, are
leaked to other organs through circulation and produce
tumor promoting effects.

7. TGF-β Pathway
• A cytokine with both pro and anti inflammatory
responses depending on the set of genes it
activates.
• The tumor suppressive effects of TGF-beta signaling
arise from its ability to induce the expression of
genes that inhibit cell proliferation, induce
apoptosis, activate autophagy, inhibit growth factor
signaling by stromal fibroblasts, suppress
inflammation, and inhibit angiogenesis. These
effects maintain homeostasis in normal tissues and
prevent the early stages of tumor formation.
• Loss of the tumor suppressive arm of the TGF-beta
signaling pathway allows cancer cells to utilize this
pathway to specifically promote processes that
support tumor progression, including the
stimulation of cell proliferation,
immunosuppression, angiogenesis, cancer stem cell
self-renewal, the epithelial to mesenchymal
transition, and metastasis.

8. NF-κB Pathway
• Basic Inflammatory pathway
• Family of 5 transcription factors
• Form hetero or homodimers
• TNF-α, IL-1β, LPS stimulate the
pathway
• IkB is inhibitor of pathway
• Control apoptosis, inflammation.

9. JAK-STAT Pathway
• Involved in processes such
as immunity, cell division,
cell death and tumour
formation.
• Cytokines such as
interleukins, interferons
and growth factors initiate
signaling
• SOCS (Suppressor of cytokine
signaling) is the inhibitor of
pathway.

10. CHRONIC INFLAMMATION
●
Upregulation of non specific proinflammatory
cytokines.
●
Increased conversion of normal cells to pre-
neoplastic foci.
●
Gain of function in somatic mutations
transforms cells for tumor initiation.

11. TUMOR ANGIOGENESIS
●
Switching on of “angiogenic switch”: balance
between
1) Tumor genes
2)Signals from tumor stroma and recruited
inflammatory cells.
3) Hypoxia
●
Endothelial cells are influenced majorly by
Vascular Endothelial Growth Factor (VEGF).

12. Cancer stem cells theory
• Among all cancerous cells, a few act as stem cells that
reproduce themselves and sustain the cancer, much like
normal stem cells normally renew and sustain our organs
and tissues.
• In metastatic tumor the reservoir of cancer cells that may
cause a relapse after surgery, radiation or chemotherapy
has eliminated all observable signs of a cancer.

13. Barriers to Metastasis

14. Migration Overview

15. INTRAVASATION
● The entry of tumor cells into circulation
is intravasation.
● The exit of tumor cells from circulation
is extravasation.
● Escape easy through abnormal
vasculature.
● Chemokines as “attractants” guide cells
in circulation.

16. SURVIVAL IN CIRCULATORY
SYSTEM
Heterotypic Foci; Tumor aggregation with
Coagulation factors.
Homotypic Foci: Tumor aggregation with
Platelets.
Tipping of balance between anti and pro apoptotic pathways; survival of anoikis

17. EXTRAVASATION
1) Increased expression of Cell Adhesion
Molecules.
2) VEGF increases vascular permeability.
3) Some tumor cells may follow White
Blood Cell motility patterns

18. PROLIFERATION
●
Final step; host tissue influences growth by
auto/para/endocrine pathways.
● e.g. Liver synthesises IGF-1 (Insulin Like
Growth Factor) which stimulates cells from
breast, colon and bladder.
●
These cells over express receptors for these
ligands.

19. THANK YOU