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95-424: Metastasis is a process of migration of tumour cells from the primary cancer site to a distant location where the cancer cells form secondary tumors. Metastatic breast cancer represents the most devastating attribute of cancer and it is considered an advanced-stage event. Human breast cancer metastasizes to multiple distant organs such as the brain , lungs , bones and liver . The classical theory developed in

190-455: A primary heterogeneic tumour . The cells which constitute the tumor eventually undergo metaplasia , followed by dysplasia then anaplasia , resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis . Some cancer cells, known as circulating tumor cells (CTCs), are able to penetrate the walls of lymphatic or blood vessels , and circulate through

285-436: A canalicular system are one metastatic process or in fact independent tumors caused by the same agent ( field cancerization ). There is a propensity for certain tumors to seed in particular organs. This was first discussed as the seed and soil theory by Stephen Paget in 1889. The propensity for a metastatic cell to spread to a particular organ is termed 'organotropism'. For example, prostate cancer usually metastasizes to

380-490: A cancer in Stage IV. The possibilities of curative treatment are greatly reduced, or often entirely removed when a cancer has metastasized. Initially, nearby lymph nodes are struck early. The lungs , liver , brain , and bones are the most common metastasis locations from solid tumors. Although advanced cancer may cause pain , it is often not the first symptom. Some patients, however, do not show any symptoms. When

475-418: A dozen are known. Human cells exhibit different kinds of motion: collective motility , mesenchymal -type movement, and amoeboid movement . Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion. All steps of

570-549: A five-fold increase in lung metastasis. Certain enhancer regions can also be analyzed and can be determined to be a crucial part of cell proliferation e.g. an enhancing region that is associated with a cancer critical gene p53 which was determined via CRISPR-Cas9. The quantitative lineage-tracing strategies have proven to be successful in resolving cell fates in normal epithelial tissues either using tissue –specific or stem-cell -specific transgenes. To conduct an inducible lineage-tracing experiment two components must be engineered into

665-408: A large extent of clonal pertinence between lesions. There are various patterns of prevalence of genetic mutations in the genomes of primary breast tumour and its metastases. It also confirms the genetic heterogeneity between the primary neoplasm of breast cancer patients and their respective metastases. Breast cancer phenotypes periodically express genes in metastasis that are indispensable for

760-458: A patient's likelihood of death. Some cancers—such as some forms of leukemia , a cancer of the blood, or malignancies in the brain —can kill without spreading at all. Once a cancer has metastasized it may still be treated with radiosurgery , chemotherapy , radiation therapy , biological therapy , hormone therapy , surgery , or a combination of these interventions ("multimodal therapy"). The choice of treatment depends on many factors, including

855-547: A primary cancerous source to nearby tissues was Ibn Sina . He described a case of breast cancer and metastatic condition in The Canon of Medicine . His hypothesis was based on clinical course of the patient. In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton

950-430: A primary tumor may appear later. The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma ), no primary tumor is found, even on autopsy . It is therefore thought that some primary tumors can regress completely, but leave their metastases behind. In other cases,

1045-414: A rate that is higher than expected by statistical chance alone. Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines and transforming growth factor beta . The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors , of which about

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1140-533: A reporter gene e.g. Beta actin GFP (Green fluorescent protein) or RFP (Red fluorescent protein). By knocking in/knocking out specific genes by homologous recombination, the extent of metastasis can be measured and new target genes identification can be achieved e.g. a gene that consistently regulates metastatic behavior of cancer cells is TGF-β1. Acute ablation of TGF-β signaling in MMTV-PyMT mammary tumor cells leads to

1235-464: A resulting acceleration in tumorigenesis. Expression of TGFβ in the breast cancer cells of MMTV-ErbB2; MMTV-TGFβ double-transgenic mice can induce higher levels of circulating tumor cells and lung metastasis. Ras gene can be combined with rtTA (reverse tetracycline transactivator) to generate bi-transgenic inducible mouse model through tetracycline-controlled transcriptional activation e.g. mice carrying TetO-KrasG12D (TOR) and MMTV-rtTA (MTB), comes with

1330-443: A technique to visualize genetically engineered cells directly in vivo. Multi step metastatic cascades can be visualized by labelling with unique fluorescent colour under fluorescence microscope . Positron emission tomography (PET), single photon emission computed tomography (SPECT) and computed tomography (CT) have been used to compare the efficiency of these in vivo imaging for detecting lesions at an early stage and to evaluate

1425-431: Is common variable immunodeficiency (CVID) where multiple autoimmune diseases are seen, e.g., inflammatory bowel disease , autoimmune thrombocytopenia , and autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis , an autosomal recessive primary immunodeficiency, is another example. Low blood levels of red blood cells, white blood cells, and platelets , rashes, lymph node enlargement , and enlargement of

1520-559: Is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, are metastases ( mets ). It is generally distinguished from cancer invasion , which is the direct extension and penetration by cancer cells into neighboring tissues. Cancer occurs after cells are genetically altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by mitosis produces

1615-583: Is a commonly used method which captures the majority of coding regions of the genome for sequencing, as these regions contain the majority of disease-causing mutations Useful for identifying mutations in specific genes • Trio or Whole-Family Analyses: In some cases, analyzing the DNA of the patient, parents, and siblings (trio analysis) or the entire family (whole-family analysis) can reveal inheritance patterns and identify causative mutations Available treatment falls into two modalities: treating infections and boosting

1710-422: Is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node . Lymphatic spread is the most common route of initial metastasis for carcinomas . In contrast, it

1805-474: Is a way of modeling human breast cancer. Mutation or over expression of oncogenes can be kept under controlled expression in a very specific cellular context rather than throughout the organism. Another way to model human breast cancer is done through the targeted inhibition of a tumor suppressor gene. Genetic studies of common diseases in humans suffer significant limitations for practical and ethical reasons. Human cell lines can be used to model disease but it

1900-1119: Is also sometimes associated with the development of autoimmune and atopic phenomena. Medical History and Physical Examination: A physician will inquire about past illnesses and family history of immune disorders to identify inherited conditions. A detailed physical examination helps recognize symptoms indicative of an immune disorder. Blood Tests: these tests are instrumental in diagnosing immunodeficiency as they measure: Infection-fighting proteins (immunoglobulins): Essential for robust immune defense, these protein levels are measured to evaluate immune function. Blood cell counts: Deviations in specific blood cells can point to an immune system anomaly. Immune system cells: These assessments are used to measure

1995-592: Is also the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells , and also impairs other immune system responses indirectly. Various hormonal and metabolic disorders can also result in immune deficiency including anemia, hypothyroidism and hyperglycemia. Smoking, alcoholism and drug abuse also depress immune response. Heavy schedules of training and competition in athletes increases their risk of immune deficiencies. The cause of immunodeficiency varies depending on

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2090-554: Is based on, respectively, whether the cause originates in the immune system itself or is, in turn, due to insufficiency of a supporting component of it or an external decreasing factor of it. A number of rare diseases feature a heightened susceptibility to infections from childhood onward. Primary Immunodeficiency is also known as congenital immunodeficiencies. Many of these disorders are hereditary and are autosomal recessive or X-linked . There are over 95 recognised primary immunodeficiency syndromes; they are generally grouped by

2185-444: Is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors , such as nutrition . Immunocompromisation may also be due to genetic diseases /flaws such as SCID . In clinical settings, immunosuppression by some drugs, such as steroids, can either be an adverse effect or

2280-416: Is difficult to study processes at the tissue level, within an organ or across the entire body. Mice can be a good representation of diseases in humans because:. Mice may not be an ideal model for breast cancer. This is mainly due to the lack of precision in many of the models. When looking at metastasis, it is difficult to determine the precise location as well as its frequency. Another issue revolves around

2375-445: Is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis. Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade. Metastasis occurs by the following four routes: The spread of a malignancy into body cavities can occur via penetrating

2470-468: Is uncommon for a sarcoma to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome . The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins , and therefore these metastatic cells can also eventually spread through

2565-484: Is used to drive the expression of mammary gland specific polyomavirus middle T-antigen , leading to a rapid development of highly metastatic tumors. MMTV-PyMT is the most commonly used model for the study of mammary tumor progression and metastasis. MMTV-PyMT mice are then crossed bred with other genetically modified mice to generate various types of breast cancer models, including: The MMTV-LTR can also be used to promote receptor tyrosine-protein kinase ErbB2 to transform

2660-501: Is widely accepted to be the result of the tumor cells migration, there is a hypothesis saying that some metastases are the result of inflammatory processes by abnormal immune cells. The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors. The research done by Sarna's team proved that heavily pigmented melanoma cells have Young's modulus about 4.93, when in non-pigmented ones it

2755-418: Is widely recognized as the benchmark method for accurately identifying individual nucleotide changes, as well as small-scale insertions or deletions in DNA. It is particularly valuable for confirming known familial genetic variations, for validating findings from next-generation sequencing technologies, and in specific scenarios that require sequencing of single genes. An example is its use to confirm mutations in

2850-487: The Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of

2945-466: The cancer exodus hypothesis , which posits that maintaining this cluster structure contributes to a higher metastatic potential. Metastasis is one of the hallmarks of cancer , distinguishing it from benign tumors . Most cancers can metastasize, although in varying degrees. Basal cell carcinoma for example rarely metastasizes. When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in

Mouse models of breast cancer metastasis - Misplaced Pages Continue

3040-469: The Bruton tyrosine kinase (BTK) gene, which are linked to X-linked agammaglobulinemia (XLA) • Targeted Gene Sequencing Panels (tNGS): This technology is ideal for examining genes in specific pathways or for follow-up experiments (targeted resequencing) from whole genome sequencing (WGS). It is rapid and more cost-effective than WGS, and because it allows for deeper sequencing. • Whole Exome Sequencing (WES):

3135-507: The ability to metastasize through the development of somatic mutations. According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy ) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential. The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that

3230-510: The blood vessel cells (endothelial cells), immune cells or stromal cells. The growth of a new network of blood vessels, called tumor angiogenesis , is a crucial hallmark of cancer. It has therefore been suggested that angiogenesis inhibitors would prevent the growth of metastases. Endothelial progenitor cells have been shown to have a strong influence on metastasis and angiogenesis. Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using

3325-404: The bloodstream to other sites and tissues in the body. This process, known respectively as lymphatic or hematogenous spread, allows not only single cells but also groups of cells, or CTC clusters , to travel. Evidence suggests that CTC clusters may retain their multicellular configuration throughout metastasis, enhancing their ability to establish secondary tumors. This perspective aligns with

3420-540: The bloodstream, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at

3515-578: The bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women, when it is called a Krukenberg tumor . According to the seed and soil theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics. For example, breast tumor cells, which gather calcium ions from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to

3610-404: The brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo . In 1928, James Ewing challenged the seed and soil theory, and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that

3705-433: The capacity to grow at an ectopic site. The metastatic progression depends on the regulation of developmental programs and environmental events. The metastatic potential of sub populations within mouse mammary cells is now considered as relatively an early event and dissemination occurs at the same time of pre invasive or micro-invasive lesions. The genetic profiles of primary and metastatic lesions in breast carcinomas show

3800-406: The circulation system, making CTCs an unlikely source of metastasis. Moreover, understanding how cancer cells adapt to the metastatic niche and remain dormant (tumor dormancy) for extended periods presents difficult questions that require further investigation. Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via

3895-406: The cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs. Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature. Additionally,

Mouse models of breast cancer metastasis - Misplaced Pages Continue

3990-430: The detection of light produced by the enzymatic oxidation of an exogenous substrate. The substrate luciferin, is oxidized to oxyluciferin in the presence of luciferase and emits light, which can be detected using an IVIS system such as a Xenogen machine. Dissociated mammary cells from MMTV-PyMT: IRES: Luc; MTB ( Internal ribosome entry site : Luciferin ) animals (which were not exposed to doxycycline) can be injected into

4085-399: The early 70's anticipated that metastasis is due to genetically determined subpopulations in primary tumours. The genetic variance between metastatic foci is significant for only particular locus and within specific cell populations or only one-cell population shows differences and some loci are divergent only in one cell subpopulation. This explains the concept of tumour heterogeneity and

4180-422: The endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets. The immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis. Epigenetic regulation also plays an important role in

4275-474: The epithelial sub types and the inability to specifically target them when targeting a mutation. An example of this would be determining the development of tumors in K14-Cre BRCA2 mice. In a standard case, the excision of BRCA2 resulted in no tumorgenesis, but if p53 was mutated and inactivated, tumorgenesis would occur. Therefore, there is not a definitive answer in terms of the origin of the tumor, due to

4370-405: The expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma . Metastases of breast cancer , medulloblastoma and prostate cancer all had similar expression patterns of these metastasis-associated genes. The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within

4465-640: The extra mutation in p53. Various mouse mammary carcinoma cell lines, like 4T1 and TS/A , are metastatic in syngeneic immunocompetent mice and can be used to identify genes and pathways involved in the metastatic process. Transplantation of tumor cells into immunodeficient mice is a tool to study breast cancer and its metastatic effects. The transplantation occurs as either allotransplants or xenographic transplants. Commonly, human cells are inoculated in an immunocompromised murine recipient. Inoculating cells through intra ductal transplantations, by cleared mammary fat pad injections or by transplantations into

4560-405: The formation of cancer fusion cells (CFCs). Understanding the enigma of cancer cell spread to distant sites, which accounts for over 90% of cancer-related deaths, necessitates comprehensive investigation. Key outstanding questions revolve around the survival and migration of cancer cells, such as the nucleus, as they face challenges in passage through capillary valves and hydrodynamic shear forces in

4655-455: The genetic state of the primary tumor reflects the ability of that cancer to metastasize. Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature." Up-regulated genes in the signature include: SNRPF , HNRPAB , DHPS and securin . Actin , myosin and MHC class II down-regulation

4750-823: The gut and lungs are seen in chronic granulomatous disease (CGD) as well. CGD is caused by a decreased production of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by neutrophils . Hypomorphic RAG mutations are seen in patients with midline granulomatous disease ; an autoimmune disorder that is commonly seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist: organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency

4845-463: The haematogenous route. This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma originating in the kidney and follicular carcinomas of the thyroid. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow . That is, hematogenous spread often follows distinct patterns depending on

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4940-413: The immune contexture, so as to foster a favourable microenvironment for secondary tumour growth. It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to

5035-489: The immune system scans the body's cells and kills neoplastic ones. They are also more susceptible to infectious diseases owing to the reduced protection afforded by vaccines . In reality, immunodeficiency often affects multiple components, with notable examples including severe combined immunodeficiency (which is primary) and acquired immune deficiency syndrome (which is secondary). B cell deficiency The distinction between primary versus secondary immunodeficiencies

5130-516: The immune system. Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in those who are immunocompromised. In the early 1950s Immunoglobulin(Ig) was used by doctors to treat patients with primary immunodeficiency through intramuscular injection. Ig replacement therapy are infusions that can be either subcutaneous or intravenously administered, resulting in higher Ig levels for about three to four weeks, although this varies with each patient. Prognosis depends greatly on

5225-602: The intended purpose of the treatment. Examples of such use is in organ transplant surgery as an anti- rejection measure and in patients with an overactive immune system, as in autoimmune diseases . Some people are born with intrinsic defects in their immune system , or primary immunodeficiency . A person who has an immunodeficiency of any kind is said to be immunocompromised . An immunocompromised individual may particularly be vulnerable to opportunistic infections , in addition to normal infections that could affect anyone. It also decreases cancer immunosurveillance , in which

5320-456: The issue in terms of modeling the amplification of HER2 in mice development. In the non-fused mouse, the mammary gland would revert to a near virgin, but with this addition the mammary gland maintained the developed function. Mouse models having two transgenes are called bi transgenic. To check the cooperation of two oncogenes, Tim Stewert and group made the first bi-transgenic mouse models in 1987, MMTV- Myc and MMTV- Ras mice were crossed with

5415-400: The lateral tail veins of immunodeficient mice on a doxycycline-free diet. No bioluminescence signal will be observed in the lungs of recipient mice until they are given doxycycline food. Bioluminescence can then be detected in the chest within 2 weeks of the start of doxycycline exposure. Luciferase is injected just before taking the images. Intravital microscopy with multi photon excitation is

5510-490: The levels of various immune cells. Genetic testing involves collecting samples from patients for molecular analysis when there is a suspicion of inborn errors in immunity. Most Primary Immunodeficiency Disorders (PIDs) are inherited as single-gene defects. The key genes associated with immunodeficiency diseases include CD40L, CD40, RAG1, RAG2, IL2RG, and ADA. Here is a summary of some methods utilized to identify genetic anomalies: Sanger Sequencing of Single Genes: Sanger sequencing

5605-500: The liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral infections due to lack of perforin are thought to be responsible. In addition to chronic and/or recurrent infections many autoimmune diseases including arthritis, autoimmune hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic inflammation of

5700-462: The location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver. Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space . The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of

5795-541: The mammary fat pads. Without this injection, the human mammary epithelial cells en-grafted onto the pad are unable to colonize and grow. The RMF/EG fibroblast must then be irradiated to allow the expression of key proteins and growth factors. After 4 weeks of development, the newly en-grafted human mammary epithelial cells expanded within the fat pad. Genetically engineered mice are constructed to model human phenotypes and pathologies . Mutant mice may include transgenes using different delivery methods: The mice undergoing

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5890-430: The metastatic cascade involve a number of physical processes. Cell migration requires the generation of forces, and when cancer cells transmigrate through the vasculature, this requires physical gaps in the blood vessels to form. Besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis. The metastatic steps are critically regulated by various cell types, including

5985-723: The metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors. These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs. A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted in an increase in E-cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι

6080-453: The metastatic pathway of cancer: the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) hypothesis (1), the cancer stem cell hypothesis (2), and the macrophage–cancer cell fusion hybrid hypothesis (3). Some new hypotheses were suggested as well, i.e., under the effect of particular biochemical and/or physical stressors, cancer cells can undergo nuclear expulsion with subsequent macrophage engulfment and fusion, with

6175-442: The metastatic process. Metastatic diversity is mediated by the activation of genes that act as coupling to organ-specific growth. The growth of lesions at the ectopic site depends on multiple complex interactions between metastatic cells and host homeostatic mechanisms. Lethal protein-protein interactions at the metastatic site aid the survival of adapted cells. Targeted expression of oncogenes in mouse mammary epithelial cells

6270-405: The mouse genome: a switch and a reporter. The switch is commonly a drug-regulated form of the bacterial enzyme Cre-recombinase. This enzyme recognizes specific sequences, called LoxP sites. Proteins that are capable of enhancing the identification of labeled cells or a specific population in unlabelled cells are encoded by the reporter transgenes. After harvesting all the ten mouse mammary glands from

6365-406: The mouse mammary epithelium. ErbB2 is an oncogene amplified and overexpressed in around 20% of human breast cancers. The mice harbouring this oncogene develop multifocal adenocarcinomas with lung metastases at about 15 weeks after pregnancy. To create a more accurate representation of HER2 gene mutations, researchers have fused the mouse gene containing neu and a rat gene containing neu. This addresses

6460-443: The myc (M) and ras (R) genes are under the control of tetracycline operators. They can also both be activated or deactivated by adding doxycycline. Other combinations in this respect are TOM; Kras; MTB, where myc can be induced and uninduced at various time points while Kras is in continuous expressed state, and myc; TOR; MTB model is vice versa. Metastatic cascade can be studied by keeping the gene activation under control or by adding

6555-409: The nature and severity of the condition. Some deficiencies cause early mortality (before age one), others with or even without treatment are lifelong conditions that cause little mortality or morbidity. Newer stem cell transplant technologies may lead to gene based treatments of debilitating and fatal genetic immune deficiencies. Prognosis of acquired immune deficiencies depends on avoiding or treating

6650-486: The nature of the disorder. The cause can be either genetic or acquired by malnutrition and poor sanitary conditions. Only for some genetic causes, the exact genes are known. There are a large number of immunodeficiency syndromes that present clinical and laboratory characteristics of autoimmunity. The decreased ability of the immune system to clear infections in these patients may be responsible for causing autoimmunity through perpetual immune system activation. One example

6745-471: The order of genetic events during tumor evolution . Many of the genes driving the growth at primary site can determine the dissemination and colonization at the ectopic site . Breast cancer is consensually considered genetically and clinically as a heterogeneous disease, in that it reflects the heterogeneity of the normal breast tissue at its origin17873350. A number of discrete genetic events have to occur in order to enable individual tumor cells that have

6840-414: The organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis . Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes. The most common sites of metastases are the lungs , liver , brain , and the bones Currently, three main theories have been proposed to explain

6935-480: The original or primary tumor . This means that if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer , not lung cancer . Metastasis is a key element in cancer staging systems such as the TNM staging system , where it represents the "M". In overall stage grouping , metastasis places

7030-963: The part of the immune system that is malfunctioning, such as lymphocytes or granulocytes . The treatment of primary immunodeficiencies depends on the nature of the defect, and may involve antibody infusions, long-term antibiotics and (in some cases) stem cell transplantation . The characteristics of lacking and/or impaired antibody functions can be related to illnesses such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example, malnutrition , aging , particular medications (e.g., chemotherapy , disease-modifying antirheumatic drugs , immunosuppressive drugs after organ transplants , glucocorticoids ) and environmental toxins like mercury and other heavy metals , pesticides and petrochemicals like styrene , dichlorobenzene , xylene , and ethylphenol . For medications,

7125-499: The patterns of spread could be better understood through a 'filter and flow' perspective. However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise. Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify

7220-457: The primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis. Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases

7315-440: The primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin (CUP) or unknown primary tumors (UPT). It is estimated that 3% of all cancers are of unknown primary origin. Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lung ", urinating blood—"probably bladder "), complex imaging will not either. In some of these cases

7410-492: The process of transgenesis are known as transgenic mice. A basic transgene has a promoter region, Protein coding sequence, Intron and a stop codon . Mouse mammary tumor virus (MMTV), is a retro virus that has been a known promoter to cause breast tumors once activated. MMTV is a heritable somatic mutagen whose target range is limited. It harbors a regulatory DNA sequence called the long terminal repeat (LTR), which promotes steroid-hormone-inducible transcription. Tumorgenesis that

7505-403: The quality of life of people with major illness, has been recommended as part of management programs for metastasis. Results from a systematic review of the literature on radiation therapy for brain metastases found that there is little evidence to inform comparative effectiveness and patient-centered outcomes on quality of life, functional status, and cognitive effects. Although metastasis

7600-441: The recipients on doxycycline food. Another tool to study breast cancer metastasis is to look for circulating tumor cells in transgenic mice e.g. MMTV-PyMT mice can respond to various therapies in shedding tumor cells in the blood leading to lung metastasis. Not only in blood but cells can be detected in bone marrow e.g. cytokeratin -positive cells in the bone marrow of MMTV-pyMT and MMTV-Neu transgenic mice were identified but not in

7695-519: The response to chemotherapy. Magnetic resonance imaging requires the use of nano-particles(liposomes) and an MRI contrast agent called gadolinium. The particles were then placed in vesicles via a polycarbonate membrane filter. The nano-particles are injected into the metastases evolved mice, and left there for twenty-four hours. These mice are then scanned, and in the imaging software there are accumulations of these particles in certain areas where cells have metastasized. Metastasis Metastasis

7790-487: The same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry , FISH ( fluorescent in situ hybridization ), and others. Despite

7885-405: The surface of the peritoneal , pleural , pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver. Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. "Positive nodes"

7980-522: The tail vein. Different organs can be seeded with breast cancer cells depending on the route of injection The specific immunodeficient mice that were used were the NOD/SCID mouse (non-obese diabetic/severe conditional immunodeficient). These mutations allow for the integration of new xenograft tissue. The mouse must first have their mammary fat pads humanized by injecting human telemorase-immortalized human mammary stromal fibroblasts(RMF/EG fibroblasts) into

8075-518: The term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system, while the term immunodeficiency generally refers solely to the adverse effect of increased risk for infection. Many specific diseases directly or indirectly cause immunosuppression. This includes many types of cancer , particularly those of the bone marrow and blood cells ( leukemia , lymphoma , multiple myeloma ), and certain chronic infections. Immunodeficiency

8170-440: The transgene expressing the reverse tetracycline transactivator (rtTA) in mammary epithelial cells. Tri-transgenic mouse models constitute of more than two genes. Multiple combinations and genetic modifications are made in such a way that either one or all the genes are put into a continuously expressed status, or in a controlled fashion to activate them at different time points. For example, TOM( TetO-myc); TOR; MTB mice, where both

8265-451: The transgenic mice, single cell suspension is usually made and transplanted either in tail vein of non transgenic recipient mice or in cleared fat pad of non-transgenic mice repopulating the mammary fat pad. These cells are then followed in the blood stream, lungs, bone marrow and liver to look for the favorable site of metastasis.these transgenic cells can be traced according to their special features of either fluorescence or induced by placing

8360-415: The tumor might just be too small and/or in an unusual location to be diagnosed. The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken. For instance, breast cancer cells look

8455-476: The type of primary cancer, the size and location of the metastases, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located. Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer and thyroid cancer , are usually curable. Palliative care , care aimed at improving

8550-447: The use of techniques, in some cases the primary tumor remains unidentified. Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor. It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop

8645-399: The wild type controls. In the absence of specific markers for mammary cells, models with genetic marking of tumor cells gives the best experimental advantage, however the low volume of peripheral blood that can be obtained from live animals limits the application of this technique. Transgenic mouse models can be imaged by various non-invasive techniques. Bioluminescence imaging relies on

8740-487: Was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor. Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis. In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in

8835-503: Was analyzed using radiography and a scanning electron microscope. These findings were published in the Public Library of Science journal. Metastasis is a Greek word meaning "displacement", from μετά, meta , "next", and στάσις, stasis , "placement". Immunodeficiency Immunodeficiency , also known as immunocompromisation , is a state in which the immune system 's ability to fight infectious diseases and cancer

8930-431: Was induced by the mouse mammary tumor virus can also be done by integration of the viral genome. The sites of integration have been known to be critical genes for cellular regulation. Whey acidic protein (WAP), is another common promoter used to generate mouse mammary cancer models. For a list of other mammary gland specific promoters and mouse models see. MMTV-PyMT is the model of breast cancer metastasis, in which MMTV-LTR

9025-439: Was only 0.98. In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They showed that there are both pigmented and non-pigmented cells in melanoma tumors , so that they can both be drug-resistant and metastatic. The first physician to report the possibility of local metastasis from

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