Part 1: Factors that Promote Malignant Tumor Formation and Metastasis

The paper intends to answer a number of questions related to pathophysiology of cancer. The first part will focus on specific factors ( at the level of the cell and the gene ) that promote malignant tumor formation and metastasis. The second part will demonstrate why the incidence of cancer 100 years ago was less than today. The last part will analyze three case studies and possible treatment options

At present, the tumor is no longer perceived as a simple accumulation of malignant cells, with the contribution of the tumor microenvironment and clonal heterogeneity playing an important role in carcinogenesis. At the same time, some researchers believe that only the first 6 of these distinctive features of a tumor can be considered fundamental, and these signs can be the basis for the development of neoplastic diseases

One of the factors responsible for metastasis is the changes in the signaling system of a tumor cell to ensure its constant proliferation (Crowe Jr, Gordon, Hubay  et al. 1991). A fundamental feature of tumor cells is their ability to support chronic proliferation. In normal tissues, growth processes and the cell cycle are carefully controlled, which provides the necessary number of cells and the corresponding tissue architecture to ensure its function. In a normal cell, stimulation for division is carried out by growth factors that bind to the receptor on the cell surface, which has an intracellular domain with tyrosine kinase activity. Activation of the tyrosine kinase domain leads to activation of the intracellular pathways that regulate the cell cycle, cell growth and other biological properties of the cell, such as energy metabolism. In the tumor, the indicated signaling system is disturbed, and the stimulation of cell growth and division occurs in the absence of external stimuli: the tumor itself becomes the “mistress of its own destiny.” At the same time, stimulation of cell division in tumor cells can be carried out in various ways. First, tumor cells can produce growth factors themselves as a result of amplification or mutation in the genes encoding growth factors. Also, tumor cells themselves can send a signal by stimulating normal tumor-associated stroma cells to the development of various growth factors necessary for them (Aguirre-Ghiso 2007). An increase in the concentration of growth factors stimulates proliferation. Secondly, an increase in the content of receptor proteins located on their surface, which leads to a hypersensitive state in relation to the growth factor, can lead to a change in the signal system in tumor cells. Third, similar effects can be caused by mutations or rearrangements in the genes encoding receptors for growth factors, leading to changes in the receptor molecule. The mutant receptor may have a constantly activated tyrosine kinase domain or be in combination with other molecules, which induces either the launch of the system regardless of the presence of the growth factor, or its launch when interacting with a nonspecific ligand (Jackson & Bartek 2009).

In recent years, studies of the tumor cell genome have shown that somatic mutations contribute to the activation of signaling systems involving growth factor receptors. It is known that about 40% of human melanomas are associated with activating mutations of the B-RAF gene, which leads to disruption of the structure of its protein, resulting in regulation carried out along the path involving RAF and is aimed at activating the MAP kinase cascade (Polyak & Weinberg 2009). In some types of tumors, mutations were found in the gene of the catalytic subunit of the phosphoinositide-3-kinase isoform (P13-kinase), which lead to a hyperactivation of the signaling cascade with the participation of the P13 kinase. It is known that mutations and rearrangements of various genes lead to the activation of signaling systems both at the level of growth factors and their receptors, and at a lower level of signal transmission along the cascade of proteins into the cell nucleus. As an example, consider the regulation of the signal system with the participation of the RAS-oncoprotein. The RAS molecule belongs to small GTP-dependent molecules that are activated during the formation of a complex with the GTP molecule and are involved in signal transmission (Friedl & Wolf 2010). The oncogenic effect is due to the fact that standard mutations of the RAS gene change the structure of its protein, preventing the dissociation of this active complex. Thus, regardless of the involvement of the ligand and receptor, the signaling system is activated at a lower level.

Part 2: Why the Incidence of Cancer Is Higher Today Than 100 Years Ago

Presence of nutrients and oxygen is also crucial in metastasis. Tumors, like normal tissues, require nutrients and oxygen for life, as well as removal of metabolic products and carbon dioxide. Neovascularization meets these needs — the formation of a network of new blood vessels in a tumor. In embryogenesis, the development of the vascular network is associated with the formation of new endothelial cells, their aggregation into tubules (vasculogenesis) and the formation of new vessels (angiogenesis). After such morphogenesis, the normal vascular network comes to rest.

Genetic instability is another factor. Tumors acquire functional features that allow malignant cells to survive, proliferate and disseminate, using various mechanisms during multi-stage carcinogenesis (Kurebayashi 2001). The most well-known property of tumor cells is genetic instability, which is caused by a change and damage to the genetic apparatus of the cell in the process of malignant growth. Changes have different forms: from random mutations in individual genes to rearrangement and rearrangement of chromosomes. However, among them such changes are rarely encountered, which can lead to the appearance of certain inherited traits (Aguirre-Ghiso 2007). Another characteristic is due to the presence of inflammation in tumors and pretumor processes, which is controlled by cells of the immune system and contributes to the progression of the tumor.

Lack of immune control is another factor. Immune has dual roles, which both opposes and contributes to the development and progression of the tumor. If the immune control is poor, then there is likelihood that the progression of the tumor may be facilitated (Jackson & Bartek 2009).

Mutation that result in structural arrangement of tumor cells would help a carcinoma in situ to become an invasive carcinoma (Raica, Cimpean & Ribatti 2009). This is attributable to the fact that the transformation of a protooncogen into an activated oncogene can be the result of structural rearrangements of the cell genome. The exchange of genetic material occurs between both homologous and nonhomologous chromosomes. As a rule, this process is a balanced reciprocating mechanism (mutually equivalent exchange of genome fragments), but DNA loss at one or both recombination points is also possible. As a result of similar events, the structure of genes (in particular, proto-oncogenes) localized in the genome rearrangement zone can undergo dramatic changes (loss of some genetic information, the formation of chimeric genes encoding hybrid proteins, and other regulatory genes entering the zone of regulatory elements ). Practically all the mentioned mechanisms of the qualitative change of oncogenes as a result of the restructuring of cellular DNA are described in human tumors. A prominent example of a specific gene translocation is Burkit’s lymphoma (LB).

The current treatment methods are designed to reverse those factors that allow proliferation of tumor cells. Some treatment methods target at restoring the immunity whereas others targets at hindering the supply of nutrients and oxygen in the affected part of the body. It should be noted that Carcinogenesis is a multistep process of accumulation of mutations and other genetic changes, leading to dysregulation of the cell cycle, apoptosis, differentiation, movement and morphogenetic reactions of the cell, as well as monitoring the integrity of the genome (Aguirre-Ghiso 2007). All this, in turn, ensures the acquisition by the cell and its descendants of a number of properties, such as self-sufficiency in proliferative signals, increased migration capacity, insensitivity to growth-inhibiting effects, lack of replicative aging, increased viability under adverse environmental conditions or intracellular damages genetic instability, etc., which determine neoplastic transformation and further tumor progression. Dysfunctions of the function of proto-oncogenes and tumor suppressors play a key role in the occurrence of the indicated properties of the neoplastic cell (Aguirre-Ghiso 2007). Current treatment targets these factors.

Part 3: Analyzing Case Studies and Possible Treatment Options

Currently, in the context of the urbanization of human life, there are more and more threats to his health. Cancer occupies the second place in United States after cardiovascular diseases. The reasons that contribute to the occurrence of a tumor are many. These include environmental factors (ultraviolet radiation, ionizing radiation, the action of carcinogenic substances, viruses, etc.) and the health status of the person himself (the occurrence of hormonal imbalance, the presence of foci of chronic inflammation, the presence of bad habits, etc. ). However, the initiating factor that triggers the process of cellular transformation is the occurrence of genetic instability in the cell. Its consequence is the appearance of mutations that are fixed in new cell generations. This leads to the further development of the tumor and its acquisition of an increasingly malignant phenotype. In addition, on the part of the immune system there is a selection of clones that are most adapted for survival in their environment. Active proliferation of these cells leads to further accumulation of mutation and, ultimately, to complete cellular transformation. A tumor from a monoclonal turns into a polyclonal, the cells change their morphology, become atypical. This is followed by the seizure by the tumor of all the new territories, the appearance of metastases and the stimulation of angiogenesis. Thus, there is a generalization of the process when the tumor captures the entire human body. Obtaining by researchers all the new data on the behavior of tumor cells in the human body, the study of their properties contribute to the development of new methodological approaches to the treatment of tumors.

Specific features that are  pollution, poor lifestyles and inactivity. Currently, there are a lot of industrial pollutants than it was in the past. It is also clear that people are more likely to engage in indulgence than they were in the past.

Consequently, some of the measures that should be taken is to engage in practices that can counteract the effects of pollutants. For example, intake of antioxidant can help in reversing the effects of free radicals. People should also reduce intake of alcohol and smoking. Alcohol is blamed for the occurrence of tumors of the oral cavity, larynx, liver, rectum and milk glands. Ethyl alcohol breaks down in the body to acetic aldehyde, which is then converted into acetic acid by the action of enzymes. Acetaldehyde is the strongest carcinogen (Junttila & Evan 2009). Alcohol is especially harmful to women, as it stimulates the production of estrogen – hormones that affect the growth of breast tissue. There is also need for exercise. Sport is on the same level with proper nutrition when it comes to oncology prevention. In the United States, one third of all deaths are attributed to the fact that patients did not follow any diet and did not pay attention to physical education. The American Cancer Society recommends training for 150 minutes a week at a moderate pace, or two times less, but more active. However, a study published in the journal Nutrition and Cancer in 2010, proves that even 30 minutes is enough to reduce the risk of breast cancer (which affects every eighth woman in the world) by 35%. Physical activity alone is beneficial. It helps maintain normal weight and prevents the development of malignant tumors.

The proto-oncogene responsible for high level of estrogen is the proto-oncogene receptor-factor 2 of human epidermal growth factor (Her-2 / neu or c-erbB-2). This mutated proto-oncogene encourages the proliferation of estrogen receptors, which in turn facilitate the growth of tumor cells.

Tamoxifen is an example of drugs used in hormonal therapy. It is the oldest and most commonly prescribed anti-estrogen drug. This is the standard hormone treatment for breast cancer in women with a preserved menstrual cycle.

An antibody to the tumor cells with a toxin attached to it is a form of immunotherapy. Immunotherapy  is a method of treatment based on the use of certain parts of the immune system to fight a tumor.

Lumpectomy followed by local radiation is a form of radio therapy. Radiation therapy (radiotherapy) for breast cancer is well tolerated by patients, does NOT lead to hair loss, does not cause nausea or vomiting, does not increase the risk of developing additional cancer, and is also absolutely painless.

I would suggest option C as the best method for treating cancer described in question #1

Estrogen Receptors (ER) regulation is not limited to direct ligand binding, since it can also be modulated in several other ways. Second messenger cyclic AMP (cAMP) regulate ER. Activation of these pathways affects the transcriptional activity of the ER, either by directly targeting the receptor, or by regulating the activity of the receptor coregulators. The method that may not work is option C because it is not easy to target the source of cyclic AMP (cAMP).

P53 acts as a DNA keeper, acting as control points in the cell cycle. When he feels abnormalities in the growth cycle, he activates the p21 gene, which binds to the process of cell division of the stimulating protein (cdk2) in order to stop the cell cycle. During the normal cell cycle, cellular enzymes initiate the DNA repair process. Consequently, if the woman has both of the cell types described in questions #1 and #3 in her tumor and also is deficient in p53 protein, it implies that deficiency of p53 protein could be the underlying reason why she developed cancer.

The third woman is most likely to have more primary cancers somewhere else in her body because increase it shows that her capacity to restore any damage on DNA is hindered by low level of p53.  

References

Aguirre-Ghiso J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 7(11):834-46

American Cancer Society (2010). Physical Activity and the Cancer Patient. Retrieved from: https://www.cancer.org/treatment/survivorship-during-and-after-treatment/staying-active/physical-activity-and-the-cancer-patient.html

Crowe Jr J. P., Gordon N.H., Hubay CA et al. (1991). Estrogen receptor for patients with carcinoma of the breast. Surg Gynecol Obstet. 173 (6): 273–8.

Kurebayashi J. (2001). Biological and clinical significance of HER2 overexpression in breast cancer. Breast Cancer.8(1):45-51

Friedl P. & Wolf K. (2010). Plasticity of cell migration: a multiscale tuning model.. J. Cell Biol. 188(1):11-9. doi: 10.1083/jcb.200909003.

Jackson S.P. & Bartek J. (2009). The DNA-damage response in human biology and disease. Nature. 461 (7267):1071-8. doi: 10.1038/nature08467.

Junttila M.R. & Evan G.I. (2009). p53 – a Jack of all trades but master of none. Nat. Rev. Cancer. 9(11):821-9. doi: 10.1038/nrc2728.

Polyak K. & Weinberg R.A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer. 9(4):265-73. doi: 10.1038/nrc2620.

Raica M., Cimpean A.M., Ribatti D. (2009). Angiogenesis in premalignant conditions. Eur. J. Cancer. 45(11):1924-34. doi: 10.1016/j.ejca.2009.04.007