Flashcards in Neoplasia Deck (17):
What the basic two component of a tumour?
All tumors have two basic components: (1) neoplastic cells that constitute the tumor parenchyma and (2) reactive stroma made up of connective tissue, blood vessels, and number of cells of the adaptive and innate immune system.
What does lack of differentiation associated with?
Lack of differentiation is associated with many morphologic changes:
- Pleomorphism – variation in size and shape.
- Abnormal nuclear morphology – the nuclear shape is variable and often irregular.
- Mitosis – many cells are in mitosis, reflecting high proliferative activity. Morphologic feature of malignancy are atypical, bizarre mitotic figures (multiple spindle).
- Loss of polarity – the orientation of anaplastic cells is disturbed.
- Rapidly growing malignant tumor develop large central ischemic necrosis.
- Rapidly growing anaplastic tumors are less likely to have specialized functional activity.
What does carcinoma in situ means?
Carcinoma in situ: when dysplastic changes involve the full thickness of the epithelium, but the lesion doesn’t penetrate the basement membrane.
What does invasive tumor means?
Invasive: once the tumor cells breach the basement membrane.
What are the most common tumour in men and women respectively?
The global impact of cancer
The most common tumors in men arise in the prostate, lung, and colon/rectum. In women, cancers of the breast, lung, and colon/rectum.
The decrease in the number of deaths caused by cervical cancer is attributable to the Papanicolaou (Pap) smear test. Stomach cancer has decreased dues to the reduction in dietary carcinogens.
Name condition that predispose to cancer?
Acquired predisposing conditions
Conditions that predispose to cancer can be divided into:
Chronic inflammation: associated with increased cellular replication. In some cases, chronic inflammation may increase the pool of tissue stem cells, which may be susceptible to transformation. Chronic epithelial injury leads to metaplasia, and long-time periods may allow cells with potentially oncogenic mutations to survive.
Precursor lesions: localized morphologic changes that are associated with a high risk of cancer. (metaplasia, hyperplasia).
Immunodeficiency: as in deficits in T-cells.
What are the four classes of normal regulatory genes?
Four classes of normal regulatory genes:
- Growth –promoting proto-oncogenes causes an increase in normal functions of the encoded gene product. These mutations cause a “gain-of function”, they can transform cells despite the presence of a normal copy of the same gene.
- Growth-inhibiting tumor suppressor genes generally cause a “loss of function”. Both alleles must be damaged before transformation can occur.
- Genes that regulate apoptosis- abnormalities that result in less death and, enhance the survival of the cell.
- Genes involved in DNA repair- impair the ability of the cell to recognize and repair nonlethal genetic mutations.
What are driver mutations?
Driver mutations are mutation that contribute to the development of the malignant phenotype. The first driver mutation that start a cell on the path to malignancy is the initiating mutation, however, it requires additional driver mutation for the development of cancer.
What are passenger mutations?
Passenger mutation- Mutation that lead to genomic instability increase the likelihood of acquiring driver mutations, and greatly increase the frequency of mutation that have no phenotypic consequence.
What are the cellular hallmark of cancer?
Self-sufficiency in growth signals – Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation.
Insensitivity to growth-inhibitory signals- due to the inactivation of tumor suppressor genes.
Altered cellular metabolism- tumor cells undergo metabolic switch to aerobic glycolysis (the Warburg effect), which enables the synthesis of the macromolecules and organelles that are needed for rapid cell growth.
Immortality – unrestricted proliferative capacity and avoid cellular senescence and mitotic catastrophe.
Sustained angiogenesis - tumors can induce angiogenesis.
Ability to invade and metastasize – arise from the interplay of processes that are intrinsic to tumor cells and signals that are initiated by the tissue environment.
Ability to evade the host immune response – exhibit a number of alternations that allow them to evade the host immune response.
Hallmark may be accelerated by genomic instability and by cancer-promoting inflammation.
What are oncogenes?
Oncogenes are genes that promote autonomous cell growth in cancer cells. Oncogenes are created by mutations in proto-oncogenes (unmutated cellular counterpart) and encode protein called oncoproteins that have the ability to promote cell growth in the absence of normal growth-promoting signals. Oncoproteins resemble the normal product of proto-oncogenes but bear mutations that are inactivated internal regulatory elements; their activity in cells doesn’t depend on external signals. Cells are freed from the normal checkpoints and controls that limit growth.
Tyrosine kinase pathway is the most frequently mutated oncogenic pathway in human neoplasms.
How can tyrosine kinase receptor be activated in cancer?
Receptor tyrosine kinases can be activated in tumors by point mutations, gene rearrangements, and gene amplifications.
- ERBB1 encode the epidermal growth factor receptor (EGFR), which is involved by point mutations in certain cancer.
- ERBB2 encodes a different membrane of the receptor tyrosine kinase family, HER2. ERBB2 gene is amplified in certain breast carcinomas, leading to overexpression of the HER2 receptor and tyrosine kinase activity.
- Gene rearrangements activate other receptor tyrosine kinases. For example, a deletion on chromosome 5 fuse part of the ALK gene with part of another gene called EML4 in a subset of lung adenocarcinomas.
What is the function of MYC oncogenes?
MYC oncogene – under normal circumstances, MYC protein concentrations are controlled at the level of transcription, translation, and protein stability. Single nucleotide polymorphisms in MYC are strongly linked to an elevated risk of cancer.
MYC activate the expression of many genes that are involved in cell growth
- Some MYC target genes, like D cyclins, are involved in cell cycle progression.
- MYC upregulates the expression of rRNA genes and rRNA processing, thereby enhancing the assembly of ribosomes need for protein synthesis.
- MYC upregulate a program of gene expression that lead to metabolic reprogramming and the Warburg effect.
- MYC can be considered a master transcriptional regulator of cell growth.
- MYC upregulates expression of telomerase.
- MYC is one of the transcription factors that can reprogram somatic cells into pluripotent.
What are the main associated mutations that affect the G1/S checkpoint?
The major cancer-associated mutations that affect the G1/S checkpoint:
- Gain-of-function mutation in D cyclin genes and CDK4, oncogenes that promote G1/S progression.
- Loss-of-function mutations in tumor suppressor genes (CDKI, P16, RB and TP53) that inhibit G1/S progression.
How can RB function be compromised?
RB function may be compromised by:
- Loss-of-function mutation involving both RB alleles.
- A shift from the active hypophosphorylated state to the inactive hyperphosphorylated state by gain-of-function mutations that upregulate CDK/cyclin D activity or by loss-of-function mutations that abrogate the activity of CDK inhibitors.
Explain APC function and how it may lead to cancer?
APC: Gate keeper of colonic neoplasia function by downregulating growth-promoting signaling pathways. Mutation of APC is associated with autosomal dominant disorder. Both copies of the APC gene must be lost for an adenoma to arise.
APC is a component of the WNT signaling pathway, which has a role in controlling cell fate, adhesion, and cell polarity during embryonic development. WNT signal through a family of cell surface receptors called frizzled (FRZ) and stimulates pathways, the central one involving β-catenin and APC. APC protein function is to hold β-catenin activity in check. In the absence of WNT signaling, APC causes degradation of β-catenin, preventing its accumulation in the cytoplasm. Signaling by WNT blocks the formation of the destruction complex, stabilizing β-catenin and allowing it to translocate from the cytoplasm to the nucleus. Once in the nucleus β-catenin forms a transcription activation complex with the DNA-binding factor TCF. The β-catenin/TCF complex promotes the growth of colonic epithelial cells by increasing the transcription of MYC, cyclin D1, and other genes. The importance of the APC/β-catenin signaling pathway in tumorigenesis is attested to by the fact that many colon tumors with normal APC genes harbor mutations in β-catenin that prevent its APC-dependent destruction, allowing the mutant protein to accumulate in the nucleus and stimulate transcription.