Biology of Cancer

Student's Name
Professor's Name
Class Information
Date
Cancer Biology
1. Dr. Richard Baer
A.
The expression of large T antigen in HDFs (human diploid fibroblasts) profoundly affects the processes of replicative senescence and genetic catastrophe. Large T antigen is a viral protein encoded by Simian Virus 40 (SV40 2-4) that can bind and inactivate tumor suppressor proteins like p53 and pRb (Moens & MacDonald). In normal HDFs, replicative senescence is a phenomenon where cells undergo a limited number of divisions due to the progressive shortening of telomeres and DNA sequences at the ends of chromosomes. When a large T antigen is introduced, it inactivates pRb, allowing cells to bypass the cell cycle checkpoint and continue to divide. However, large T antigen does not prevent telomere shortening, leading to critically shortened and dysfunctional telomeres. This sets the stage for genetic catastrophe, where cells may undergo chromosomal instability, aneuploidy, and accumulate DNA damage. While these cells may continue to replicate, they often harbor significant chromosomal aberrations, which can affect their function and potentially contribute to cancer development. Immortalized cells by large T antigen generally exhibit an abnormal karyotype, with a mix of numerical and structural chromosomal alterations that reflect their genomic instability.
B
Constitutive expression of TERT (telomerase reverse transcriptase) in HDFs has a different effect on replicative senescence and genetic catastrophe. TERT, serving as the catalytic component of telomerase, has a pivotal role in extending telomeres. In regular human diploid fibroblasts (HDFs), replicative senescence ensues as telomeric DNA gradually diminishes with each cell division. The introduction of TERT enables cells to extend their telomeres, counteracting the shortening process and permitting more cell divisions. TERT-immortalized cells maintain longer telomeres, preventing telomere-related senescence (Dratwa et al. 1). However, they are not entirely immune to genetic catastrophe, as other contributing factors can lead to DNA damage accumulation over time. However, unlike large T antigens, the genetic disaster in TERT-immortalized cells is not directly linked to telomere shortening. Karyotypes of TERT-immortalized cells may appear more stable and resemble the diploid, euploid state typical of normal cells. This stability is a result of maintaining telomere length and minimizing telomere dysfunction-related genetic chaos.
2. Dr. Allison Taylor
A
Depleting Mad2 causes premature sister chromatid separation by disrupting the spindle assembly checkpoint (SAC) and interfering with kinetochore-microtubule attachments. This leads to chromosome mis-segregation and aneuploidy. Another gene, BubR1, when depleted, can also disrupt the SAC, resulting in similar premature chromatid separation.
B
B-1
"MIN" stands for Microsatellite Instability, while "CIN" stands for Chromosomal Instability.
B-2
Microsatellite instability (MIN) involves alterations in the length of short, repetitive DNA sequences (microsatellites) in a cell's genome, often caused by defects in DNA mismatch repair mechanisms. This instability results in changes in microsatellite length and an increased mutation rate. In contrast, Chromosomal Instability (CIN) refers to changes in the number or structure of entire chromosomes, such as aneuploidy or loss of heterozygosity (Tijhuis et al. 2-4). It is associated with defects in processes like mitosis and DNA damage response.
B-3
Distinguishing between MIN and CIN is vital because they have different implications for cancer development and therapy. MIN is commonly found in hereditary non-polyposis colorectal cancer (HNPCC) and some sporadic tumors, and it may affect a patient's response to immunotherapies. In contrast, CIN is more prevalent and plays a significant role in various cancer types. Understanding which type of genomic instability is present can influence treatment decisions and prognosis for cancer patients.
C
Key Difference
Aneuploidy is defined as an abnormal chromosome number within a cell or organism where the count differs from the typical diploid number. It often arises from nondisjunction during cell division, leading to improper chromosome separation. Aneuploid cells can possess extra chromosomes (trisomy) or lack a chromosome (monosomy). In contrast, Chromosomal Instability (CIN) represents a cellular state characterized by a high frequency of chromosome missegregation during cell division, increasing the chances of aneuploidy. CIN is more concerned with the process of chromosome division and distribution during mitosis and meiosis.
One Way to Measure Each
Aneuploidy assessment often involves karyotyping, which examines chromosomes. Techniques like FISH, CGH, or next-gen sequencing are used (Xu et al. 4). CIN evaluation monitors aneuploid cell prevalence over time. Methods include FACS or cytogenetic analysis, checking for chromosome abnormalities.
3. Dr. Shan Zha
A.
Lynch syndrome, an inherited genetic condition, heightens the risk of various cancers, including colorectal, endometrial, ovarian, stomach, small intestine, hepatobiliary, upper urinary tract, brain, and skin cancers (Bhattacharya and McHugh 1). Early detection and surveillance are critical for individuals with a Lynch syndrome family history, allowing proactive steps to treat and lower the risk of these linked malignancies. To confirm the diagnosis of Lynch syndrome in a cancer cell line, one could utilize molecular testing. Microsatellite instability (MSI) analysis and immunohistochemical staining for MMR proteins like MLH1, MSH2, MSH6, and PMS2 are commonly employed diagnostic approaches. Eukaryotic MMR distinguishes template DNA from newly synthesized DNA by recognizing and correcting mispairs in the newly synthesized strand. It identifies the strand with nicks and discontinuities, which are typically present in the newly synthesized strand post-replication, allowing for the discrimination between the template and newly synthesized strands.
B.
DNA double-strand break repair events at the IgH locus in B cell lymphomas are often associated with class switch recombination (CSR) and somatic hypermutation (SHM). CSR is the process that enables the rearrangement of the IgH gene to switch the class of immunoglobulins produced by B cells, contributing to antibody diversity and function. SHM introduces mutations in the variable region of the IgH gene to enhance antibody affinity (Petrova et al. 3). The repair pathway primarily responsible for these breaks is non-homologous end joining (NHEJ), which rejoins the DNA ends at the breakpoints during CSR and SHM by directly ligating the broken DNA ends without the use of extensive homology. This process allows for the error-prone nature of CSR and SHM, which is essential for antibody diversification.
4. Dr. Adolfo Ferrando
A
Wang et al.'s findings are significant within clonal evolution models of resistance to chemotherapy and targeted drugs. These models propose that cancer cells are not a homogenous population but consist of various subpopulations or clones with distinct genetic characteristics. Over time, these subclones can evolve and adapt in response to treatment, leading to drug resistance. In this study, the identification of resistance mechanisms to non-covalent BTK inhibitors through on-target BTK mutations and downstream PLCγ2 mutations exemplifies the clonal evolution model. The development of resistance occurs through the emergence and selection of specific genetic alterations within cancer cell populations under the selective pressure of the drug (Wang et al. 2 - 3). As these resistant subclones increase, they become dominant, leading to treatment failure. This phenomenon is consistent with clonal evolution models where subpopulations with genetic changes confer a survival advantage in the presence of the drug outcompete sensitive cells. Moreover, the ability of specific mutations to confer resistance to both covalent and non-covalent BTK inhibitors underscores the adaptability of cancer cells in the face of different therapeutic challenges. These findings emphasize the importance of considering clonal evolution in the design and application of targeted therapies to predict and overcome potential resistance mechanisms, ultimately improving the efficacy of cancer treatment strategies.
B
Tzoneva et al. elucidated the impact of NT5C2 mutations in relapsed acute lymphoblastic leukemia (ALL), revealing a paradoxical phenomenon where these mutations induce resistance to chemotherapy, specifically 6-mercaptopurine (6-MP) while impairing leukemia cell growth and leukemia-initiating cell activity. The study found that the Nt5c2 p.R367Q mutation, prevalent in relapsed ALL, led to heightened purine export to the extracellular space and depletion of the intracellular purine nucleotide pool, ultimately imposing a fitness cost on the mutant cells (Tzoneva et al. 5-6). These findings highlight the intricate interplay between resistance mechanisms and cellular fitness during the clonal evolution of leukemia. The study further suggests that inhibiting guanosine synthesis via inosine-5′-monophosphate dehydrogenase (IMPDH) holds the potential for enhancing cytotoxicity against NT5C2-mutant leukemia cells, thereby offering insights into novel therapeutic strategies for managing chemotherapy resistance in ALL and potentially in other cancers as well.
C
Oshima et al.'s study contributes significantly to the comprehension of clonal evolution models regarding resistance to chemotherapy and targeted drugs in acute lymphoblastic leukemia (ALL). Their integrative approach, combining a thorough exploration of mutational landscapes with genome-wide CRISPR screens on gene-drug interactions across seven ALL chemotherapy agents, sheds light on the intricacies of chemoresistance in the disease's progression. Through the analysis of diagnostic and relapsed samples, the research uncovers distinct mutational mechanisms associated with different disease stages, exemplifying the evolving landscape of clonal evolution as genetic alterations accumulate over time (Oshima et al. 3). Furthermore, the revelation of shared and drug-specific pathways influencing chemotherapy responses underscores the multifaceted nature of clonal expansion as diverse subclones contend under selective pressures created by drug regimens. This study provides essential insights into the genetic and functional foundations of chemotherapy resistance in ALL, paving the way for more effective therapeutic approaches that target specific resistance mechanisms, addressing the challenges posed by clonal evolution in the context of cancer therapy, an...