Tumor Biology for Clinicians PDF

💊 PG 2 Date @November 12, 2024 Status Done Topic Tumor biology for clinicians Tumor biology for clinicians Cancer develops in cells that are: highly proliferative (lymphocytes, intestines) frequently exposed to...

💊 PG 2 Date @November 12, 2024 Status Done Topic Tumor biology for clinicians Tumor biology for clinicians Cancer develops in cells that are: highly proliferative (lymphocytes, intestines) frequently exposed to environmental carcinogens (lungs, intestine) proliferative activity is under hormonal control (breast, prostate) Hallmarks of cancer The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. They include: sustaining proliferative signaling evading growth suppressors resisting cell death enabling replicative immortality inducing angiogenesis activating invasion and metastasis PG 2 1  Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress … has added two emerging hallmarks of potential generality to this list: reprogramming of energy metabolism evading immune destruction. PG 2 2  Cancer associated genes Oncogenes: (positive regulators of proliferation or survival) Products of qualitative (gain of function mutations) or quantitative changes in genes (proto-oncogenes) controlling cell proliferation or survival. Their activity is dominant over the endogenous, normal gene meaning that a mutation in one allele is sufficient. (e.g. EGFR, Ras, Myc, …) Tumor suppressor genes: (negative regulators of proliferation or survival) Products of qualitative (loss of function mutations) or Quantitative changes in genes that negatively control cell proliferation or survival. Their activity is typically recessive over the endogenous, normal gene meaning that both alleles must be PG 2 3  mutated. (e.g. Rb, p53, CKI, …) Clonal evolution in cancer Cancer is a multi-step process, before it develops we need the accumulation of several mutations. The key point is that DNA replication and repair is a tightly regulated system, therefore the problem arises when there is a problem in the DNA repair systems. This allows mutations to accumulate in key genes and over time, these mutations can be selected for and allow for the development of cancer. Driver vs. passenger mutations Driver mutations are mutations that contribute to cancer. These give the cells an advantage. Passenger mutations are neutral mutations that don’t offer any advantage to the cell. They may also be discarded later PG 2 4  Oncogenic events: not a linear phenomenon There is no unimodal relation between these concepts (hallmarks of cancer) but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell… Tumors are very heterogenous, they are made up of a diverse population of cells each evolving separately. These differences allow the tumor to adapt and survive in various conditions and locations in the body. Tumor development is a very dynamic process, therefore this heterogeneity is favorable. This complex and constantly changing interaction between cells within a tumor must be taken into consideration when developing therapies. PG 2 5  Metastasis Linear progression Historically, metastasis was thought to occur as a linear process meaning that metastatic ability represents the final stage of tumor evolution. However this is not always true, in reality the metastatic potential of a tumor can vary greatly and some tumors are metastatic from the very beginning. Parallel progression This model is based on the fact that metastatic cells can evolve alongside the primary tumor from the very beginning. If this is true, there needs to be a more aggressive approach for treatment. However it is important to note that parallel progression isn’t true for all cancers. PG 2 6  Invasion-metastasis cascade This is a very complex process that requires the ability to adapt to several harsh and diverse environments. PG 2 7  Note that even if the cells successfully extravasate, you might not always see the metastasis because, for example, the cancer cells might not survive or some cells might enter a dormant state or get stuck in the early stages of the cell cycle, thus not able to proliferate. A reduction in immune surveillance that helps control cancer growth might favor the reactivation of the metastasis. So if a patient becomes immmunosuppressed due to aging, long-term corticosteroid use, chemotherapy, etc. this can create an environment where metastasis is more likely to take hold and spread. In addition infections and other factors that cause inflammation can promote metastasis as neutrophils can produce factors that support tumor growth. The role of the microenvironment earlier, reductionist view of a tumor as nothing more than a collection of relatively homogeneous cancer cells, whose entire biology could be understood by PG 2 8  elucidating the cell-autonomous properties of these cells (is no longer acceptable). …….In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer……….. Over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues. When viewed from this perspective, the biology of a tumor can only be understood by studying the individual specialized cell types within it as well as the “tumor microenvironment” that they construct during the course of multistep tumorigenesis. Numerous stromal components (fibroblasts, ECM proteins, neo-formed lymphatic and blood vessels, inflammatory cells) of NON neoplastic origin (thus not carrying mutations) associate with the growing tumor in a sort of neo-formed organ PG 2 9  This “realization” has made a shift in therapies, now shifting towards therapies that aim to modify the tumor’s microenvironment This is a major area of research, in fact genetic screening is also being done on the surrounding cells of the microenvironment and what has been found is that the presence of certain cell types within the microenvironment is closely linked to patient prognosis. The microenvironment also plays a role in the production of growth factors. In fact, the tumor doesn’t always produce the growth factors themselves, instead it can also manipulate the cells around itself to produce the growth factors. Due to the fact that tumors are not always entirely independent in their growth, the microenvironment is a potential therapeutic target. Many tumors have receptors on they surface that respond to growth factors. It's not that the tumor cells themselves have mutations that make them constantly grow; rather, they often have mutations that enhance their response to growth factors produced by surrounding cells. An example of this therapy is anti-angiogenesis therapy → we target the process that tumors use to create new blood vessels What is cancer? Cancer is the outcome of a multistep process Cancer is not a single disease (variable pathogenesis, diagnosis, treatment) Paradigmatic example for translating research findings from the laboratory into clinical applications A modern oncologist must know about: Molecular Biology PG 2 10  Experimental models Clinical trials Precision medicine PG 2 11 PG 2 12  History PG 2 13  A cell line is the first subculture obtained from a primary culture. PG 2 14  Generally, cells can be isolated from different animal tissues and primary cultures can be maintained in vitro. However, the first subculture obtained from the primary culture has a finite lifespan. In few instances, (e.g. when a cell line undergoes a genetic transformation), the growth of this cell line may become indefinite giving rise to a continuous cell line that can grow grow through serial passaging. Considerations: not all cells, even cancer cells will grow in a petri dish (very rare for a tumor to generate a cell line) if the cells grow on plastic with a basic medium, this means that they are far more aggressive than the original tumor because they can survive and grow in conditions far less rich then blood. cell lines are not always representative of the original tumor Results and limitations of the initial empirical approach The limitations of this approach are obvious. The main one is that it selects drugs active on fast-growing cells (P388 and L1210), and with a growth fraction of 100% (i.e. all cells are cycling). While this approach can be effective in identifying drugs that are active against leukemia and lymphomas, it penalizes the search for drugs that are active against most solid, slow-growing adult cancers with most dormant cells (G0). With this initially purely empirical approach, modified for the first time in the mid-1970s, over 400,000 compounds have been screened, and most of the drugs currently in use in oncology have been developed. there is a limitation when testing drugs. Drugs that kill these cells will only show effectiveness in stopping cell proliferation. (first drugs discovered using this system were for leukemia, lymphoma, and other fast proliferating cancers- PG 2 15  solid tumors are more challenging to find treatments for as they are less proliferative) PG 2 16 PG 2 17 PG 2 18  Pre-screening is done with human cell lines. In addition the pre-clinical model using mice was introduced. This allows for testing on the efficacy and toxicity Some consequences on the results of the empirical approach The major consequence is certainly a bias in favor of active compounds on actively proliferating cells. In fact, most of the current drugs are 'anti- proliferative‘. Many agents have non-specific cytotoxicity. the tissues most affected by these drugs are the highly proliferating ones like: skin, hair, blood cells, stem cells, spermatozoa thus common side effects include: hair loss, diarrhea, mucositis, infertility, and cytopenia (leukopenia, thrombocytopenia, and anemia) The mechanism of action of the drug is initially unknown, just as the cellular target is also unknown (empirical approach). However, most of the drugs currently in use in oncology are derived from this screening which began in the 1950s. Only in recent years has the landscape changed from empirical screening to targeted screening. PG 2 19  Targeted approach → targeting the BCR-ABL fusion protein to treat CML even if we sequence the genomes of all tumors, we don’t know which mutations are driving the cancer PG 2 20  Rapid improvements in our understanding of human biology are paving the way for a dramatically different future for medicine Unique characteristics of every patient and the heterogeneity of every tumour are now defining treatment strategies to reduce side effects and improve outcomes Moving away from a ‘one-size fits all’ approach and finding ‘the right treatment for the right patient at the right time’ This is the mantra of Precision Medicine Benefits to patients (and physicians): Improved outcomes through greater efficacy, better benefit: risk ratios, avoidance of over- or under-treatment, etc Also benefits for payers and the healthcare system, potentially reducing costs and delivering system efficiencies PG 2 21  more than one mutation can be relevant, we may need multiple therapies to address all the key drivers tumors are dynamic, the genetic signature of a tumor at diagnosis may not be the same after treatment, it is crucial to continuously monitor the tumor’s evolution more omics to come PG 2 22  Multi-omics approach: RNA this gives insight to which genes are being expressed. Note that high expression of a gene may not always be linked to mutations DNA methylation mircoRNAs proteome PG 2 23