Lecture 8: Tumor Microenvironment Flashcards
Stromal Compartment
The region of a tumor composed of cancer cells non-cancerous tissues making up the main component of the tumor microenvironment
Tumor stroma respond to anticancer therapies by inducing _______________, which can lead to fatal disease
Therapeutic resistance
Tumor stroma composition
Extracellular matrix and a variety of non-cancerous populations neighboring cancer cells such as fibroblasts, vascular endothelial cells, immune cells, adipocytes, and nerves.
Paraneoplastic syndromes
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.
What do paraneoplastic syndromes often indicate
A previously undiagnosed tumor. Rapid recognition, however, facilitates an early treatment.
Normal fibroblast structural roles
-Support and maintenance of tissue
-Wound healing processes of most organs
-Synthesis of collagens for ECM deposition
-Restriction of tumor initiation and growth
Roles of recruited stromal fibroblasts in supporting carcinomas
-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
1961 experiment on tumor stroma evidence
Basal cell carcinomas of the skin were excised from patients and then reimplanted in normal areas of the skin elsewhere in the same patient.
Results of 1961 tumor stroma experiment
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.
Consequence of PTEN deletion in stromal fibroblasts
Stimulation of tumor growth
Cancer’s with abundant stroma in ratio of neoplastic cells to stroma
Breast cancer, colon carcinoma, adenocarcinoma of stomach
Cancer’s with reduced stroma in ratio of neoplastic cells to stroma
Hodgkins lymphoma and benign hemangioma
Desmoplasia
Reactive fibrotic response in malignant neoplasms by excessive deposition of collagen around cancer cells, resembling abnormal wound healing.
Dense collagenous stroma/ Desmoplastic response
Feature of many carcinomas, particularly breast and pancreas. Can often be responsible for the clinical presentation of a tumor as a lump.
Primary cause of desmoplastic stroma
Cancer-associated fibroblast “Activation” to myofibroblasts with high production of collagen.
Desmoplasia association in prostate cancer
Associated with poor prognosis and adverse clinicopathologic factors
E-Cadherin role in Epitheloial-to-mesenchymal transition
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.
EMT role in desmoplastic stroma
EMT enables dissociation of tumor cells from the primary tumor mass invasion through the ECM, intravasation into blood vessels and colonization of distant organs.
Composition of Tumor Microenvironment (TME)
Comprised of ECM & non-cancer cells neighboring the tumor epithelial cells vasculature, stromal, immune cells
7 Roles TME plays in tumorigenesis
- Activation of stromal cells (Myofibroblasts)
- Excess extracellular matrix (ECM)
- Evading immune response (inflammation)
- Tumor angiogenesis
- Recruitment of distant cells (Vascular endothelial)
- Secretion of growth factors that stimulate epithelial growth
- Stemness (cancer stem cell activation)
Primary function of Cancer-associated fibroblasts (CAFs)
Regulating inflammation; participating in wound healing; integrating collagen and protein to form ECM fiber network; escaping damage.
Primary function of immune & inflammatory cell
Treatment of wound healing & infection; clearing dead cells and cellular debris; having double effect on tumor formation
Primary function of the blood & lymphatic vascular networks
Require nutrients and oxygen; evacuating metabolic wastes and carbon dioxide; helping escape immune surveillance
Primary function of adipose cells
Producing circulating blood estrogen; a major energy source; relating with inflammation; recruits immune cells; supports vasculorgenesis
Primary role of neuroendocrine cells
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
Adipocytes role in TME for pre-cancer
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
Adipocytes role in TME during cancer
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
Consequences of crosstalk between adipocytes and cancer cells
Change in function and phenotype in BOTH cell types
Role of neuronal innervation in metastasis and primary tumors
- Peripheral nerves emerge as regulators of cancer initiation, progression, and metastasis
- Cancer induces nerve outgrowth in TME by release of neurotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination
- Sympathetic nerves drive tumor angiogenesis via liberation of noradrenaline
Experimental evidence for role of neurons in TME
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
Stimulation of endothelial cells by noradrenalin (NA) released from adregenic nerves
Induces an angiogenic swithc that fuels tumor growth and metastasis. The presence of sensory nerves in TME can also participate in cancer pain
Role of paracrine signaling by tumor stroma for cancer growoth
- Primary tumor secretes macrophages to microenvironment and cells increase metastatic potential by increasing tumor cell migration, invasion, and intravasation
- Macrophages also increase angiogenesis thereby increasing the targets for metastatic cell escape
- Tumor associated fibroblasts secrete chemokines and VEGH for angiogenesis
Colony-stimulating factor 1 (CSF1) & epidermal growth factor roles
These factors and their receptors are expressed differentially on carcinoma cells and macrophaghes, resulting in movement of cancer cells towards macrophages.
Expression of C-X-C chemokine receptor 4 (CXCR4)
Production of cognate ligand stromal cell-derived factor 1 (SDF1/CXCL12) that contributes to directional cancer cell migration.
Metastatic progression is a core contributor to overall cancer mortality and is often closely associated with the activation of stem programs due to __________
The growth factor secreted by the immune and stromal cells
Dormant micrometastases
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.
Virchow’s irritation theory for cancer (1858)
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.
Normal wound healing
- Rapid hemostasis
- Appropriate inflammation
- Mesenchymal cell differentiation in myofibroblasts proliferation, and migration to the wound site.
- Suitable angiogenesis
- Epithelial cells: prompt regrowth of epithelial tissue over the wound.
CSR gene pattern
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.
Rationale for targeting tumor stroma
-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.
