Hypoxia-mediated Selection of Cells with Diminished Apoptotic Potential in Solid Tumours

Besides inducing apoptosis and controlling the cell cycle, p53 has been demonstrated to be a central component and key regulator of the metabolic stress machinery. The metabolic balance between glycolysis and oxidative phosphorylation is heavily coordinated by p53 activity, which is activated by

Cancer, as a general term of many fatal and protean diseases as well as a challenging puzzle in medical field in the world, causes death of a multitude of people. According to the statistics of National Cancer Institute, the cancer mortality is 171.2 per 100,000 men and women per year (based on 2008-2012 deaths) [1], which is indeed a horrible figure. Cancer might occur in everyone's life, like an invisible murder, taking many people's life away ruthlessly. Once I visited a friend of my mother, a bony HCC patient who had to bear the unimaginable agony of his body especially the liver area and the psychological pain, underwent a number of harmful chemotherapies in hospital or to be more exact, a white prison. Therefore, what is cancer? It is

The body is affected on a cellular level by cancer. Going more into detail, cancer is caused by an error in the replication process of a cell. The cell is changed to rapidly and relentlessly reproduce more replicas of its’ mutated self. These cancer cells, along with the power to multiply quickly, have the innate ability to ignore commands from the body about destruction. If there are ever too many cells in the body, messages are sent to perform apoptosis. Apoptosis is where the cell commits suicide, but cancer cells can become immune to this signal. Together the two combine to make an unstoppable cell growing factory.

This elimination of oxygen allows the cancer cells to form. All cancer forms develop due to two reasons: acidic blood and oxygen deficits or hypoxia. The cancerous cells cannot continue to exist in high amount of oxygen, since they do not breathe oxygen, which means that they are anaerobic cells. Only glucose helps these cells to exist.

The factors limiting the growth of malignant neoplasm include the basal membrane and various components of the surrounding stroma, increased interstitial pressure, limited oxygen supply to tumor cells and the formation of active oxygen forms, hypoxia conditions, and permanent exposure to immune system cells. Given the intra-tumoral heterogeneity, in the struggle for survival, some tumor cells may be subjected to regression and death, while other cells, which resist powerful, counteracting micro-environmental factors, gain an aggressive phenotype and the ability of metastatic progression. Invasive tumor growth is enabled by the detachment of malignant cells from the tumor mass due to a reduction in or complete loss of intercellular adhesion molecules, and, therefore, the cells gain the ability of anomalously high motility enabling penetration through the stiff structural elements of the surrouss means the ability to thrust aside adjacent tissues, and also to actively invade and, therefore, destroy these

Interest in cancer has grown recently as it has been one of the most fatal causes of death yet; there has only recently been an advance in the understanding the cellular basis of cancer. Due to today’s understanding of cancer it has been acknowledges that the disease disregards the rules of normal cell division, as a group of abnormal cells grow uncontrollably. Cancer is described as being the unnecessary development of cells within the body. Individual’s genetic tendency contains a significant role in the cancerous growths, as the genetic information of an individual can’t be controlled. In order to understand the cellular basis of cancerous cells and there difference between normal cells, there are certain aspects in which need to be addressed that being; DNA replication and translation, oncogenes and protogenes, tumor suppression genes, how tumour cells work, apoptosis and cell death, blood vessel growth (angiogenesis) and metastasis.

The availability of oxygen and nutrients supplied by the blood vessels are essential both to the normal and abnormal cells, Folkman’s study on cancer and its relationship to vessels showed him and others that the response of tumour to hypoxia leads

Among the most important advances in cancer research is the idea of apoptosis and the genes that control it, where they have a profound effect on the malignant phenotype. P53 was the first tumor suppressor gene linked to apoptosis. Mutations in this tumor suppressor gene occur in the majority of human tumors and are often associated with advanced tumor stage and poor patient prognosis. Studies using p53 knockout mice demonstrated that endogenous p53 could participate in apoptosis. Also, it is now known that a lot of factors and stimuli can activate p53 to promote apoptosis, including hypoxia and mitogenic oncogenes.

Tumor hypoxia, a Common feature in 90% solid tumors like HCC is intricately associated with more malignancy, therapeutic resistance and poor patient survival 4. In order to survive under such reduced oxygen concentration, tumor cell adapts some transcriptional expression where Hypoxia-inducible factor (HIF) is a key transcriptional factor 31.

This article tends to explain to the reader how Warburg theory applies in understanding cancer research. It explains how tumors can be generated from the various cells. Through this article, the reader can understand that oxygen plays a significant role when it comes to the prevention of cancer in the body. Thompson, a cancer biologist, and Dang, a cell biologist, helps us to understand this concept by developing models. These models can prove that Warburg theory is practicable and that mutation, and not mitochondria, is a cancer multiplier. It also explains the role of hypoxia-inducible factor 1 in cancer research.

Apoptosis is basically a checkpoint that is placed at the end of G1, G2, and S. If the cell detects anything wrong, it will explode. Most cancer cells are created when apoptosis can’t be triggered in a damaged cell due to mutation, and reproduces indefinitely, using up massive amounts of energy, serving no purpose, and building

In the year 2016, the American Cancer Society projected that 595,690 individuals will pass due to cancer and 1,685,210 individuals will develop a new cancer case. Many scientists such as Dr. Bert Vogelstein or Dr. Robert Weinburg have been trying to understand the mechanism behind cancer and create therapeutic agents that could potentially prevent this disease from occurring. The most novel and studied gene and protein in regards to cancer is p53. The protein was discovered in the 1970s when research was focused on cancers that are caused by viruses and was later identified as being a tumor suppressor (1). One of the most studied areas of cancer is how p53 functions and its role in the cell cycle which has led to studies that target p53 as a therapeutic agent for cancer (1). In the year 2001, it was found that the protein product of the gene hSIR2SIRT1, which is a homolog of S. cerevisiae Sir2 protein, deacetylates the p53 protein and allows for either cell growth arrest or apoptosis (2). Due to this finding, the Sirtuin 1 protein has been heavily studied and even been targeted as being a therapeutic target for varying diseases and even involved in the phenomena known as caloric restriction (3–5). ¬

The oxygen supply in cancer cells is determined by their vascular network. As pre-malignant lesions they are highly vascularized but as they keep growing their vascular network becomes very irregular and inefficient. There is a basement membrane that separates the hyperplastic epithelia from the vascular stroma where the blood supply is. As the tumor cells keeps growing the distance from its blood supply increases. This greater distance means that there will be less oxygen and less glucose available. As a result, cancer cells select for traits that will help them have better fitness in a scarce environment. This could be an explanation of why cancer cells select for the more inefficient and toxic glycolytic phynotype.

In addition, several tumor suppressor genes are frequently altered in PDAC. The most mutated one is p53 which is inactivated in 75%. (15) P53 has a vital role in regulating cellular stress and determines cell fate by inducing programmed cell death in response to DNA damage. (14) Studies revealed that mutations in p53 results in accumulation of the mutant protein within the cell nucleus and decrease tumor’s sensitivity of chemotherapy as a result of losing its apoptotic function. (16) SMAD4 is another tumor suppressor gene which is mutated in around 55% of the tumor. (14) Inactivation of SMAD4 leads to the loss of a significant part of cell growth suppression. (16) The third essential tumor suppressor gene is CDKN2A that is altered in 26% of the tumor. (17) CDKN2A control cell cycle and when it is silenced it increase tumor size the likelihood of metastases. (14,16)

The rapid proliferation of tumour cells soon exhausts the existing vascular supply and brings about a hypoxic environment in the TME (Coussens and Werb, 2005). Endothelial and stromal cells form a