Cancer Flashcards
How do we view cancer from an immunological perspective?
From an immunological perspective, cancer cells can be viewed as altered self cells that have escaped normal growth-regulating mechanisms.
This makes recognition and response by the immune system challenging; while we want to be rid of these cells, we also do not want to mistakenly stimulate an autoimmune attack on healthy tissues.
What is a neoplasm?
Cells that give rise to progeny with the ability to expand in an uncontrolled manner will produce a tumor or neoplasm.
What is the difference between benign and malignant tumors?
- A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue is said to be benign.
- A tumor that continues to grow and becomes
progressively more invasive is called malignant. It may also metastasize - invade other
distant tissues. The term cancer refers specifically to a malignant tumor.
Describe the formation of a metastatic tumor from a normal cell in short.
- A single cell develops altered growth properties at a tissue site, which may be corrected via DNA repair.
- The altered cell proliferates, forming a mass of localized tumor cells, or a benign tumor.
- The tumor cells become progressively more
invasive, spreading to the underlying basal lamina. The tumor is now classified as malignant. - The malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body.
How are cancers classified? Provide three examples.
Cancers are classified according to their embryonic tissue origin:
- Carcinomas are tumors that develop from epithelial origins, e.g. skin, gut, or epithelial linings
- Sarcomas derive from mesodermal connective tissue, e.g. bone, fat, and cartilage tissue
- Lymphomas, myelomas, and leukemias derive from hematopoietic stem cells: Leukemias are early stage development of bone marrow cells, lymphomas and myelomas arise from cells after migration out of bone marrow.
Remember, cancers can arise from any cell type!
DNA alterations can induce malignant transformation, give two examples of transformation inducers.
- Chemical substances (such as formaldehyde, benzene, and some pesticides)
- Physical agents (e.g., asbestos)
- Ionizing radiation
- Viruses and other infectious agents (eg EBV, HBV/HCV, HPV - all sharing the property of integrating into the host cell genome and disrupting chromosomal DNA)
Normal cellular genes that are associated with the formation of cancer fall into three major categories based on their activities, which?
- Oncogenes enhance cell survival when their control mechanisms fail (before they mutate they are referred to as proto-oncogenes that encode for proteins such as transcription factors, growth factors (and their receptors), or intracellular signaling molecules)
- Tumor-suppressor genes allow cancer cell survival when they fail, usually inhibitors of cell growth and proliferation, such as during DNA repair or in blocking progression through cell cycle checkpoints.
- Apoptosis gene problems can also lead to abnormal cell survival.
What is a common symptom of having developed a lymphoma?
Lymphomas arise after progenitors have left bone marrow and spread through the lymphatic system. They proliferate in secondary lymph organs; swollen lymph nodes are common early symptoms.
What is a common symptom of having developed a myeloma?
Myelomas arise after progenitors have left bone marrow, they arise from uncontrolled proliferation of fully differentiated B cells. They spread through the blood; migrate to bone marrow and produce a mutated form of antibody called M protein.
Malignant cells display alterations in six key cellular processes, which?
Malignant cells display alterations in key cellular processes and microenvironmental conditions:
- cell fate decisions
- genome maintenance
- cell survival
- genetic instability
- metabolic changes
- immune response patterns.
Tumor antigens can be divides as tumor-specific antigens and tumor associated antigens, give two examples of each.
Tumor-specific antigens (unique to tumors - easily identifiable for the immune system):
- proteins exclusively expressed by infected tumor cells
- novel peptides generated by mutations (presented on MHC I - natural targets for immune system since their “foreign”)
Tumor associated antigens (not foreign - harder for the immune system to recognize):
- proteins inappropriate for the current developmental stage (oncofetal tumor antigens)
- overexpressed wild-type self proteins
There are three proposed pathways for how the immune system controls or inhibits cancer, which?
Three proposed pathways for how the immune system controls or inhibits cancer:
- Destroying viruses that are known to transform cells.
- Eliminating all pathogens and downregulating inflammation.
- Identifying and eliminating pre-cancerous and transformed cells – immunosurveillance.
The immune system is very effective in immunosurveillance and combating neoplasmic cells so that it never progress, but when it fails it can go fast.
Describe the term “immunoediting”.
Immunoediting is a model that describes how the developing tumor-specific immune response identifies and kills cells (elimination, or immune surveillance), maintains a balance between death and survival of cancer cells (equilibrium), and also fosters the selection and survival of cells that develop immunoevasive mutations (escape).
Which are the main innate inhibitors of cancer?
the main innate inhibitors of cancer are NK cells and macrophages, but also APCs.
- NK cells were among the first cell types to be recognized for their ability to destroy cancer cells.
- Macrophages often cluster around tumors and produce proinflammatory cytokines that correlate with tumor regression.
- M1 macrophages, cross-presenting DCs, and NK cells produce cytokines that help elicit strong TH1 and CTL responses.
Which are the main adaptive inhibitors of cancer?
T cells, specifically tumor-specific CD8 T cells are very important in the battle against cancer, but also NKT cells. B cells also play an important role, generating antitumor Ab against tumor-specific Ag - which promotes tumor-cell recognition and lysis.
Note: Tumor enhancing antibodies can also arise; these may block CTL access to tumor Ag, which is very problematic.
Which are the most central cytokines in cancer inhibition?
The cytokines most connected with antitumor responses include:
- Both type I and type II IFNs, mainly IFN-g, all interferon types enhance tumor-cell removal activities of immune cells.
- IL-12: Encourages DCs to activate strong TH1 and CTL responses.
- also TNF-α, which was named for its anticancer activity. When injected into tumor-bearing animals, TNF-α induces hemorrhage and necrosis of the tumor. However, TNF-α was later shown to have both tumor-inhibiting and tumor-promoting effects (complex)
All these cytokines are associated with strong TH1-cell and CTL responses.
Some inflammatory responses can promote cancer, give an example of how.
Chronic inflammation increases cellular stress signals, which in turn can lead to genotoxic stress (e.g., ROS, RNS) that is increasing mutation rates in cells - which can lead to mutations that can lead to cancer.
This in combination with growth factors and cytokines released by cells during the inflammatory response often induce proliferation, and if this is provided to an already neoplastic cell, this can accelerate cancer formation.
inflammation is also pro-angiogenic and pro-lymphangiogenic, meaning it increases growth of blood and lymphatic vessel growth, allowing for greater tumor-cell invasion into surrounding tissues.
How can antibodies be tumor enhancing?
- Antibodies may bind and block tumor Ag that would otherwise be targeted by CTLs.
- They may form complexes with free tumor Ag which can impair antitumor activities of NK cells and macrophages, e.g. by binding to Fc receptors on these cells.
How can immune cells suppress cancer?
The presence of immunosuppressive cells (e.g., MDSCs, M2 macrophages, and T cells) and the cytokines they produce (e.g., IL-10 and TGF-β) in the tumor microenvironment fosters tumor survival and immune evasion.
Also upregulation of PD-1 in tumor cells can stimulate Tregs to supress immune system even more.
Describe two way for how cancer cells can evade the immune system.
- Reduced MHC expression (usually following mutations in TAP, β2-microglobulin) in tumor cells makes them poor targets for CTLs, a very good evasion possibility. This doesn’t protect from NK cells tho, but:
- decreased expression of NK activating receptor ligands makes them poor targets for NK cells - also a reason for successful mutations leading to cancer.
- Also tumor-cell resistance to apoptosis can occur by:
- expression of mutated or absent death receptors, for example, Fas and TRAILR
- upregulation of anti-apoptotic mediators
- downregulation of pro-apoptotic mediators
What role can co-stimulatory molecules play in the development of cancer?
Tumor antigen specific T cells can not be activated if all three signals for T cell activation are present, so for example the loss of CD80 - which is the ligand to the co-stimulatory receptor CD28 on T cells - leads to no signal “ for T cells, resulting in anergy. This mutation renders the cancer virtually “safe” from CTLs which are the main cancer fighting cells, so they can expand and grow a lot.
Many cancer cells are also successful due to upregulation of inhibitory receptors.There is a cancer immunotherapy that builds on this. What is this immunotherapy?
Immune checkpoint inhibitors, which are antibodies towards PD-1 which block the inhibitory signal from T cell PD-1 interaction with up-regulated PDL1 ligand, allowing T cells to attack.
Cancer drug therapies generally fall into four loosely organized categories, which?
- Chemotherapies aimed at blocking DNA synthesis and cell division
- Hormonal therapies, which interfere with tumor-cell growth
- Targeted therapies such as small molecule inhibitors of cancer
- Immunotherapies, which induce or enhance the antitumor immune response
Combinations are often effective.
Give two examples of cancer immunotherapies.
- monoclonal antibodies that target specific surface molecules (either naked or with toxins conjugated)
- CAR T cells generated by adding a chimeric
receptor recognizing a tumor antigen to autologous T cells that are expanded and later re-infused - checkpoint blockade, where mAbs recognizing co-inhibitory molecules (e.g., CTLA-4, PD-1, or PD-L1) are used alone or in combination to interrupt negative regulation of tumor-specific T
cells. - adoptively transferred autologous DCs that have been loaded with TAAs and expanded in vitro, followed by reinfusion into the patient
- adoptively transferred T cells that have been collected from the patient and expanded or modified in vitro, and then reintroduced;
