1.7 Transformation

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Transformation results from a series of events that alters a cell's properties by promoting genetic changes, which results in the acquisition of cancer cell like properties (1). Transformed cells possess unique characteristics that allow them to grow beyond normal growth limits. These cells lack contact inhibition, are anchorage-independent, and are capable of growing on top of each other in a limitless fashion (2). In other words, they are not inhibited by density or contact with other cells (3). Unlike normal cells, they are able to grow and divide even in the absence of signals from external growth and survival factors. All of these characteristics give transformed cells the potential to develop into benign tumours. Transformation typically occurs from spontaneous or induced permanent mutations to the genome, resulting in heritable DNA or gene expression changes. These changes are usually the result of carginogens from the environment, creating mutations that alter normal cellular processes (2).

 

This video illustrates the differences between transformed cancerous cells and normal cells, including impaired contact inhibition.

Here is another video that depicts contact inhibition in normal cells versus transformation cells, in animation and in vitro.

 

It takes multiple changes to convert normal cells into transformed cells. In 1953, Nordling observed that it typically takes 6 events to form cancer in humans (1). Knudsen then hypothesized that creation of a cancerous cell requires multiple genetic changes (1). There are multiple changes in cellular processes or environmental triggers that can cause cancerous cell transformation (1).

 

In the environment, there are two general classes of compounds that are involved in transformation: initiators and promoters. Initiators are substances that can create a heritable change in DNA, which can lead to cancerous growth (1). An example of an initiator is cigarette smoke or other chemical carcinogens. Promoters are substances that can induce cell division (1). These substances are typically cellular products or derived from cellular products. A good example of a promoter would be a growth factor secreted to induce cell division. The example below illustrates that it takes multiple events for a transformed cell to become cancerous as well as the role of promoters and initiators in the transformation process (4).

 

Figure 1.7.1. Transformation of cells by exposure to initiator and promoter compounds. Treating healthy skin cells with only initiators or only promoters does not change the growth phenotype. Treating with an initiator followed by multiple treatments with promoters on an adjacent spot leads to no change. Treating with an initiator then multiple treatments with promoters at the same location (same cells) over time leads to papilloma formation. Over time without further treatment, the papilloma regresses. Treating as in the previous case with long-term promoter treatment maintains the papilloma.  Treating as before and then exposing the papilloma to iniators causes carcinoma formation (i.e. a second genetic hit unleashes more agressive growth). Released under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0).

 

The initator and promoter example focuses on environmental carcinogens that produce changes in the cells. However, changes or mistakes in cellular processes (especially in DNA replication) can also initiate transformation by altering the genome to create mutations. This occurs through the activation of oncogenes or inactivation of tumor suppressor genes (TSGs) (3). No single mutation is sufficient to induce tumors because normal cells have multiple mechanisms to regulate their growth, all of which must be bypassed to allow cancerous growth. Multiple mutations are needed so that each of these processes becomes disregulated, allowing tumour formation. No specific single mutation is necessary for tumour growth, as there are many different genes involved in each regulatory pathway whose disruption can lead to disregulation of the process. These transforming mutations occur in oncogenes or tumour supressor genes. Oncogenes aid in the transformation process in a gain of function manner when they are activated. Tumor suppressor genes cause transformation when they are inactivated, allowing cancerous cells to bypass the normal controls that regulate their growth (2). Chapters 2 and 3 contain more in-depth analysis and information on the role of oncogenes and TSGs in tumourigenesis and cancer progression.

 

Transformation via miRNA

 

MicroRNA (miRNA) misregulation has been associated with the process of transformation. These small non-coding RNA molecules are implicated in post-transcriptional regulation of various mRNA molecules by binding complementarily to such target RNA molecules, which results in down-regulation or degradation of the target mRNA. Involvement of miRNA in the process of transformation was initially hypothesized since several mRNA encoding genes that are misregulated in cancers undergo post-transcriptional miRNAs processing. Kumar et al. subsequently show that miRNA misregulation (specifically the decreased levels of miRNA maturation) promotes transformation and tumorigenesis, rather than miRNA misregulation being a consequence of an already-existing transformed phenotype (6). The mouse models in which Kumar et al. disrupted miRNA processing exhibited tumours, which were more invasive and had accelerated kinetics compared to control tumours, indicating that miRNAs have a role in transformation and tumorigenesis(6).

                                      

Although miRNA upregulation is seen in some cancers and downregulation in others, most cancer types exhibit a decreased activity level of miRNA (19). One of the mechanisms of miRNA deregulation is by transcription factors present in cancer cells. For example, the transcription factor Myc (which is oncogenic in nature) and the loss of p53 (tumor suppressive transcription factor) downregulates miRNA expression and may transform normal cells (19). Due to the involvement of miRNA in cancer, further research into manipulating miRNA levels in cancer cell lines may be used as a treatment method. By deactivating oncogenic miRNA or stimulating the activity of tumor suppressive miRNA, tumor formation may be lessened (19).

 

Transformation via Inflammation

 

Transformation can be instigated by the inflammatory cascade. There is currently a strong link between chronic inflammation and cancer (7). This link is present at various stages of tumor development, from initiation to metastasis, and treatment (18). Conditions that induce chronic inflammation are often associated with cancers in the affected tissues. Examples include: irritable bowel syndrome and colon cancer (8), Helicobacter pylori infection and gastric cancer (9), and asbestos exposure and lung cancer (10).

 

The triggering of chronic inflammation or any actions through the inflammatory mechanisms, either by bacterial or viral infection or by a tumor promoter (e.g. tobacco) seems to be the key aspect that increases the risk of cancer (18). However, it is important to note that some chronic inflammatory diseases could actually work the opposite way and reduce cancer risk (e.g. psoriasis) (18). Tumor-associated inflammatory responses can also occur. These responses depict the pro-tumorigenic outcome of the body's natural response against other tumors or from a reaction to cancer therapy. Overall, pro-tumorigenic responses from inflammation and anti-tumorigenic responses from other aspects of the immune system both exist throughout tumor progression (18).

 

The reactive oxygen species (ROS) generated by immune cells during inflammation are genotoxic and may trigger mutations in DNA that can induce transformation (11). Reactive nitrogen intermediates (RNI) can also be generated and may induce damage to the DNA and cause genomic instability (18). Further, Iliopoulos et al. (2009) demonstrated that NF-κB activation and IL-6 expression in non-transformed breast cells lead to a transformative epigenetic signature and phenotype (12). The pro-inflammatory signaling molecule IL-6 and, to a lesser extent, IL-17 and IL-23 have been shown to drive cell cycle progression, leading to transformation (13). Inflammation can also protect already transformed cells from cell death. Pikarsky et al. (2004) showed that suppression of inflammation by TNF-α inhibition in hepatocarcinoma-prone mice lead to the apoptotic death of transformed cells (14). In addition, adhesion molecules generated during the immune response can further add to the metastatic potential of a cancer cell and help generate tumor niches (15). Inflammation can provide the initial mutation events that create a transformed cell, the proper microenvironment for survival, cell division, and metastasis, making it an important physiological event in the development of cancer.

 


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