Lecture 8: Tumor Microenvironment

Question 1

Stromal Compartment

Answer 1

The region of a tumor composed of cancer cells non-cancerous tissues making up the main component of the tumor microenvironment

Question 2

Tumor stroma respond to anticancer therapies by inducing _______________, which can lead to fatal disease

Answer 2

Therapeutic resistance

Question 3

Tumor stroma composition

Answer 3

Extracellular matrix and a variety of non-cancerous populations neighboring cancer cells such as fibroblasts, vascular endothelial cells, immune cells, adipocytes, and nerves.

Question 4

Paraneoplastic syndromes

Answer 4

Indirect manifestations of cancer due to functional peptides/hormones produced by a tumor or due to cross reactivity between tumor and host antigens that provoke auto-reactive antibodies that can attack a variety of tissues such as immune reactions and brain tissue.

Question 5

What do paraneoplastic syndromes often indicate

Answer 5

A previously undiagnosed tumor. Rapid recognition, however, facilitates an early treatment.

Question 6

Normal fibroblast structural roles

Answer 6

-Support and maintenance of tissue
-Wound healing processes of most organs
-Synthesis of collagens for ECM deposition
-Restriction of tumor initiation and growth

Question 7

Roles of recruited stromal fibroblasts in supporting carcinomas

Answer 7

-ECM remodeling/excess collagen production
-Pro-angiogenesis: Growth factor secretion such as VEGF for tumor vasculature
-Immunomodulation: Secretion of pro-inflammatory chemokines and cytokines
-Extensive reciprocal signal interactions with cancer cells and crosstalk with other cells in the TME

Question 8

1961 experiment on tumor stroma evidence

Answer 8

Basal cell carcinomas of the skin were excised from patients and then reimplanted in normal areas of the skin elsewhere in the same patient.

Question 9

Results of 1961 tumor stroma experiment

Answer 9

Those implanted with stroma yieled robustly growing carcinoma cells while those implanted without concomitantly implanted stroma failed to grow and only produced vacuolated cells and cell debris.

Question 10

Consequence of PTEN deletion in stromal fibroblasts

Answer 10

Stimulation of tumor growth

Question 11

Cancer’s with abundant stroma in ratio of neoplastic cells to stroma

Answer 11

Breast cancer, colon carcinoma, adenocarcinoma of stomach

Question 12

Cancer’s with reduced stroma in ratio of neoplastic cells to stroma

Answer 12

Hodgkins lymphoma and benign hemangioma

Question 13

Desmoplasia

Answer 13

Reactive fibrotic response in malignant neoplasms by excessive deposition of collagen around cancer cells, resembling abnormal wound healing.

Question 14

Dense collagenous stroma/ Desmoplastic response

Answer 14

Feature of many carcinomas, particularly breast and pancreas. Can often be responsible for the clinical presentation of a tumor as a lump.

Question 15

Primary cause of desmoplastic stroma

Answer 15

Cancer-associated fibroblast “Activation” to myofibroblasts with high production of collagen.

Question 15

Desmoplasia association in prostate cancer

Answer 15

Associated with poor prognosis and adverse clinicopathologic factors

Question 16

E-Cadherin role in Epitheloial-to-mesenchymal transition

Answer 16

Acts as a cell adhesion molecule and its loss will signal the process of EMT transition where cells acquire the ability to migrate and become invasive.

Question 17

EMT role in desmoplastic stroma

Answer 17

EMT enables dissociation of tumor cells from the primary tumor mass invasion through the ECM, intravasation into blood vessels and colonization of distant organs.

Question 18

Composition of Tumor Microenvironment (TME)

Answer 18

Comprised of ECM & non-cancer cells neighboring the tumor epithelial cells vasculature, stromal, immune cells

Question 19

7 Roles TME plays in tumorigenesis

Answer 19

1. Activation of stromal cells (Myofibroblasts)
2. Excess extracellular matrix (ECM)
3. Evading immune response (inflammation)
4. Tumor angiogenesis
5. Recruitment of distant cells (Vascular endothelial)
6. Secretion of growth factors that stimulate epithelial growth
7. Stemness (cancer stem cell activation)

Question 20

Primary function of Cancer-associated fibroblasts (CAFs)

Answer 20

Regulating inflammation; participating in wound healing; integrating collagen and protein to form ECM fiber network; escaping damage.

Question 20

Primary function of immune & inflammatory cell

Answer 20

Treatment of wound healing & infection; clearing dead cells and cellular debris; having double effect on tumor formation

Question 21

Primary function of the blood & lymphatic vascular networks

Answer 21

Require nutrients and oxygen; evacuating metabolic wastes and carbon dioxide; helping escape immune surveillance

Question 22

Primary function of adipose cells

Answer 22

Producing circulating blood estrogen; a major energy source; relating with inflammation; recruits immune cells; supports vasculorgenesis

Question 23

Primary role of neuroendocrine cells

Answer 23

Extending lumina and adjacent epithelial cells; regulating secretion and motility; controlling lung branching morphogenesis; providing a protecting niche for a subset of lung stem cells

Question 24

Adipocytes role in TME for pre-cancer

Answer 24

In obesity, hypertrophied adipose tissue depots are characterized by a state of low-grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development

Question 25

Adipocytes role in TME during cancer

Answer 25

De-lipidation. Cancer associated adipocytes (CAA) release fatty acids through lypolysis which are then transferred to cancer cells and used for energy production through beta-oxidation. The abundant availability of lipids from adipocytes in the TME supports tumor progression an uncontrolled growth

Question 26

Consequences of crosstalk between adipocytes and cancer cells

Answer 26

Change in function and phenotype in BOTH cell types

Question 27

Role of neuronal innervation in metastasis and primary tumors

Answer 27

1. Peripheral nerves emerge as regulators of cancer initiation, progression, and metastasis
2. Cancer induces nerve outgrowth in TME by release of neurotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination
3. Sympathetic nerves drive tumor angiogenesis via liberation of noradrenaline

Question 28

Experimental evidence for role of neurons in TME

Answer 28

Denervation delated tumor initiation and metastasis in mouse models. Denervation of cholinergic nerves or knockout of type 1 muscarinic acetylcholine receptors (CHRM1) inhibited tumor cell dissemination

Question 29

Stimulation of endothelial cells by noradrenalin (NA) released from adregenic nerves

Answer 29

Induces an angiogenic swithc that fuels tumor growth and metastasis. The presence of sensory nerves in TME can also participate in cancer pain

Question 30

Role of paracrine signaling by tumor stroma for cancer growoth

Answer 30

1. Primary tumor secretes macrophages to microenvironment and cells increase metastatic potential by increasing tumor cell migration, invasion, and intravasation
2. Macrophages also increase angiogenesis thereby increasing the targets for metastatic cell escape
3. Tumor associated fibroblasts secrete chemokines and VEGH for angiogenesis

Question 31

Colony-stimulating factor 1 (CSF1) & epidermal growth factor roles

Answer 31

These factors and their receptors are expressed differentially on carcinoma cells and macrophaghes, resulting in movement of cancer cells towards macrophages.

Question 32

Expression of C-X-C chemokine receptor 4 (CXCR4)

Answer 32

Production of cognate ligand stromal cell-derived factor 1 (SDF1/CXCL12) that contributes to directional cancer cell migration.

Question 33

Metastatic progression is a core contributor to overall cancer mortality and is often closely associated with the activation of stem programs due to __________

Answer 33

The growth factor secreted by the immune and stromal cells

Question 34

Dormant micrometastases

Answer 34

Cancer cells often enter dormancy to evade immune attacks. Once in a new location, these dormant cancer cells (DCC’s) receive signal from the surrounding tissue where they gain the ability to re-enter the cell cycle. Chronic inflammation can also reactivate DCC’s that can trigger tumor development.

Question 35

Virchow’s irritation theory for cancer (1858)

Answer 35

Based on the observation that neoplastic lesions often develop at sites of chronic irritation. Concluded that irritation of any type (mechanical, chemical, or thermal) was the essential factor of neoplastic tissue proliferation. Meaning tumors are wounds that never heal.

Question 36

Normal wound healing

Answer 36

1. Rapid hemostasis
2. Appropriate inflammation
3. Mesenchymal cell differentiation in myofibroblasts proliferation, and migration to the wound site.
4. Suitable angiogenesis
5. Epithelial cells: prompt regrowth of epithelial tissue over the wound.

Question 37

CSR gene pattern

Answer 37

Presumably reflected the states of stromal fibroblasts and related cell types within these tumors. Shows a greater probability for developing metastases in the years following initial treatment. Also exhibited higher mortality rates.

Question 38

Rationale for targeting tumor stroma

Answer 38

-Tumor stroma responds to anticancer therapies by inducing therapeutic resistance that can ultimately lead to fatal disease
-Anticancer therapies should target both cancer cells and stromal compartments to be effective and result in improved patient.