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Can a tumor begin to form without any genetic mutations? I'm specifically interested in a tumor which could later lead to cancer.
This is a very interesting question, and one that has been at the heart of cancer research for a long time. I think it separates into three issues.
Are there non-genetic mechanisms that can induce uncontrolled cell proliferation?
Yes, at least in experimental settings. There are many viruses that induce proliferation in its host cell, and viral genes / proteins have been identified that can disable the host cell's cell cycle regulation machinery. A well-studied example is the SV40 Large-T gene (from Simian Virus 40); this gene can be expressed in cells to cause cell proliferation in a transient, reversible manner, and it does so by interacting with host proteins, without causing genetic changes. See for example this article.
Can such genetically normal cells progress to form tumors?
It depends on what you mean by "tumor". To my knowledge, tumors large enough to be a serious medical problem are always found to be genetically altered in one way or another. There are plenty of viruses that cause tumors in humans, for example Epstein-Barr and papilloma (HPV) virus, but in all cases viral sequences are found integrated into the host genome. This may be because development of large tumors requires many cell division, and any non-genetic change that drives proliferation is likely to be lost on the way.
On the other hand, HPV virus frequently causes warts, which technically are small benign tumors. As far as I know, no genetic modification of the host cell is required for this to happen; rather, the virus replicates from its own separate DNA while simultaneously driving keratinocyte cell proliferation to cause these growths. So this example shows that small "tumors" can be formed without any genetic cause. Perhaps there is a limit on how large tumors can grow without genetic changes.
Can genetically normal cells form cancer, meaning a malignant (invasive) tumors?
No, as far as I know, this has never been observed. Large, malignant tumors without genetic changes are unlikely for the reasons above. There are cases of metastatic cancer where the primary tumor is so small that it cannot be located, but in these cases the metastatic cells are again genetically altered. Experimentally, it is possible to produce invasive behavior in cell lines by expressing oncogenes like ras, but these genes are mutated to begin with. Also, normal cells have mechanisms that detect such alterations, causing senescence, and they must first be inactivated by mutations. Transformation to an invasive phenotype is not usually caused by viruses, probably because it would give no advantage to the virus (unlike cell proliferation).
For more information, Robert Weinberg's Cancer textbook does a good job of discussing these issues. This article also provides a historical perspective of tumor virology with some interesting pointers.
- Given the incidence rate of cancer, it is likely that usually multiple somewhat independent events have to occur, so that cancer forms (see the famous interpretation of the underlying data/thinking by Hanahan et Weinberg 2000 )
- Epigenetic changes seem to be a likely factor contributing to cancer ( summary of an experiment, where they are also causal/inducing )
- People have been suspecting, with good rationale, that the intrinsic variability of (bio)chemical reactions, which often only involve a small number of copies of the involved molecules, could contribute to cancer ( e.g.: Ansel et al. 2008 ). (Note: directly addressing this hypothesis for cancer by experiments would be quite difficult / perhaps-impossible)
- None of the above should be seen as opposing the relevance of genetic mutations
I would go with NO for the simple reason: For a cell to become malignant (cancerous), cells need to break several barriers. One is to be able to activate telomerase, an enzyme that restores telomeres and enables infinite cell divisions.
Another important part is to be able to ignore apoptosis. This is programmed cell death. Specific cell signals lead to systematic chemical changes and cell death. So for cancer cells, it is important to be able to ignore this signal.
These are only two basic things, there are more, for a cell to become cancerous.
Changes to this will necessarily lead to change in DNA. However, I don't have direct proof and I don't work in this area.
Endometriosis fits this definition. In many ways endometriosis is like metastatic cancer. Endometriosis is the movement of fragments of endometrial lining out of the uterus (prsumably via the fallopian tubes) to other sites in the body. There these fragments implant and call in a vascular supply to feed them. Endometriosis fragments usually cause trouble in the abdomen and pelvis but they can go anywhere, including skin, lung and the brain. Metastasis is not an inappropriate name for this.
These fragments grow and stick things together (like intestines), causing the same sort of problems that cancer can cause in these sites. They bleed with the menstrual cycle. Endometriosis in the lung can cause hemoptysis. The masses of endometrial tissue and the blood and fluid they accumulate can become endometriomas: benign tumors which are accumulations of tissues and blood which can be mistaken for cancerous tumors on imaging.
The endometrial tissues causing this are not mutant. They are just in the wrong place. Endometriosis can, however, give rise to a true cancer. Clear cell carcinoma is known to form in deposits of endometriosis.
Cancer cells change the order of the cell cycle stages.
Cancer cells continue to divide even when they come into contact with other cells.
Cancer cells are not regulated because they have lost the ability to control cell division.
Passes on genetic information to offspring
Acquires materials and energy to manufacture cellular components
Unresponsive to changes in the internal and external environment
Adapts to changes in its environment
Acquires materials and energy to manufacture cellular components
Sister chromatids separate
Cell performs all of its normal functions
Chromatin becomes tightly coiled and visible
A cell malfunctions and unregulated cell division occurs.
Genetic material was copied without errors.
Cell division is regulated.
A cell malfunctions and apoptosis is triggered.
Promotes the growth of local capillaries to grow toward the tumor
Causes normal cells to release chemical signals to promote blood vessels to cancer cells
Allows for oxygen to reach the tumor
Allows for oxygen to reach the tumor
A numerical staging system describes the degree to which cancer has spread.
Staging helps describe where cancer has spread and whether it is affecting other parts of the body.
The lower the cancer stage of breast cancer, the more severe the form of cancer.
Staging helps describe where cancer has spread and whether it is affecting other parts of the body.
What is the size of the tumor
What is the degree to which it has invaded nearby tissues
Is the cancer present in nearby lymph nodes
To what extent has the cancer metastasized to other organs of the body?
adjustments in physiological processes to respond to changes that disrupt the internal environment
operating at the same set of conditions as the external environment
maintaining a narrow range of internal conditions to optimize the body's performance
allowing for large fluctuations in which enzymes of the body are still able to function correctly
utilizing negative feedback mechanisms to maintain internal conditions
maintaining a narrow range of internal conditions to optimize the body's performance
utilizing negative feedback mechanisms to maintain internal conditions
Brain cancer may place pressure on areas of the brain that regulate bodily functions and disrupt their regulation.
With lung cancer, the tumor increases the number of airways and increases the amount of oxygen available to the body.
Cancer in the bone marrow may prevent white blood cells from forming, reducing the ability of the immune system, and leaving the body open to infection.
Cancer in the bone marrow may prevent white blood cells from forming, reducing the ability of the immune system, and leaving the body open to infection.
The MET gene is located on chromosome 7q31.2 and encodes a 1,390 amino-acid protein. The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits, which are disulfide-linked to form the mature receptor. Two transcript variants, which encode different isoforms, have been found for this gene.
The beta subunit of MET possesses tyrosine kinase activity and was identified as the cell-surface receptor for hepatocyte growth factor (HGF). MET transduces signals from the extracellular matrix into the cytoplasm by binding to the HGF ligand it also regulates cell proliferation, scattering, morphogenesis, and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain, which provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PI3KR1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC. The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities.
Prevalence and Founder Effects
A novel pathogenic variant was identified in exon 16 of the MET gene in two large hereditary papillary renal carcinoma (HPRC) families in North America. Affected members of the two families shared the same haplotype located within and immediately distal to the MET gene, suggesting a common ancestor (founder effect). However, HPRC families with identical germline MET pathogenic variants who do not share a common ancestral haplotype have also been reported.
Penetrance of MET Pathogenic Variants
HPRC is highly penetrant (approaching 100%).[5-7]
To date, all cases of HPRC present with type 1 papillary renal cell carcinoma.[5,6,8-10] Extra-renal manifestations associated with this condition have not been reported.
- Park M, Dean M, Kaul K, et al.: Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A 84 (18): 6379-83, 1987. [PUBMED Abstract]
- Komada M, Hatsuzawa K, Shibamoto S, et al.: Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett 328 (1-2): 25-9, 1993. [PUBMED Abstract]
- Bottaro DP, Rubin JS, Faletto DL, et al.: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251 (4995): 802-4, 1991. [PUBMED Abstract]
- Gherardi E, Birchmeier W, Birchmeier C, et al.: Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12 (2): 89-103, 2012. [PUBMED Abstract]
- Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58 (8): 1719-22, 1998. [PUBMED Abstract]
- Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]
- Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [PUBMED Abstract]
- Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [PUBMED Abstract]
- Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PUBMED Abstract]
- Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
A new study reveals a vulnerability of cancer cells
Cancer cells. Credit: Tel Aviv University
What makes cancer cells different from ordinary cells? Can these differences be used to strike at them and paralyze their activity? This basic question has bothered cancer researchers since the mid-19th century. The search for unique characteristics of cancer cells is a building block of modern cancer research. A new study led by researchers from Tel Aviv University shows, for the first time, how an abnormal number of chromosomes (aneuploidy) could become a weak point for these cells. The study could lead to the future development of drugs exploiting this vulnerability to eliminate the cancer cells.
The study, which was published in Nature, was conducted in the laboratory of Dr. Uri Ben-David of the Sackler Faculty of Medicine at Tel Aviv University, in collaboration with six laboratories from four other countries (the United States, Germany, the Netherlands, and Italy).
Aneuploidy is a hallmark of cancer. While normal human cells contain two sets of 23 chromosomes each—one from the father and one from the mother—aneuploid cells have a different number of chromosomes. When aneuploidy appears in cancer cells, not only do the cells "tolerate" it, but it can even advance the progression of the disease. The relationship between aneuploidy and cancer was discovered over a century ago, long before it was known that cancer was a genetic disease (and even before the discovery of DNA as hereditary material).
According to Dr. Ben-David, aneuploidy is actually the most common genetic change in cancer. Approximately 90% of solid tumors, including breast cancer and colon cancer, and 75% of blood cancers, are aneuploid. However, our understanding of the manner in which aneuploidy contributes to the development and spread of cancer is limited.
In the study, the researchers used advanced bioinformatic methods to quantify aneuploidy in approximately 1,000 cancer cell cultures. Then, they compared the genetic dependency and drug sensitivity of cells with a high level of aneuploidy to those of cells with a low level of aneuploidy. They found that aneuploid cancer cells demonstrate increased sensitivity to inhibition of the mitotic checkpoint—a cellular checkpoint that ensures the proper separation of chromosomes during cell division.
They also discovered the molecular basis for the increased sensitivity of aneuploid cancer cells. Using genomic and microscopic methods, the researchers tracked the separation of chromosomes in cells that had been treated with a substance that is known to inhibit the mitotic checkpoint. They found that when the mitotic checkpoint is perturbed in cells with the proper number of chromosomes, cell division stops. As a result, the chromosomes in the cells separate successfully, and relatively few chromosomal problems are created. But when this mechanism is perturbed in aneuploid cells, cell division continues, resulting in the creation of many chromosomal changes that compromise the cells' ability to divide, and even cause their death.
The study has important implications for the drug discovery process in personalized cancer medicine. Drugs that delay the separation of chromosomes are undergoing clinical trials, but it is not known which patients will respond to them and which will not. The results of this study suggest that it will be possible to use aneuploidy as a biological marker, based on possibility to find the patients who will respond better to these drugs. To put it another way, it will be possible to adapt drugs that are already in clinical trials for use against tumors with specific genetic characteristics.
In addition, the researchers propose focusing the development of new drugs on specific components of the mechanism of chromosomal separation, which were identified as especially critical to aneuploid cancer cells. The mitotic checkpoint is made up of several proteins. The study shows that the aneuploid cells' sensitivity to inhibition of the various proteins is not identical, and that some proteins are more essential to cancer cells than others. Therefore, the study provides motivation for developing specific drugs against additional proteins in the mitotic checkpoint.
"It should be emphasized that the study was done on cells in culture and not on actual tumors, and in order to translate it to treatment of cancer patients, many more follow-up studies must be conducted. If they hold true in patients, however, our findings would have a number of important medical implications," Dr. Ben-David says.
CONTROVERSIES IN GLIOBLASTOMA MULTIFORME STEM CELLS
The ”stem cell-centric“ model of cancer originally envisioned an adult stem cell as the target of oncogenic hits. Accordingly, the malignant transformation of these cells gives rise to cancer cells that maintain stem-like traits. This has fostered the translation of knowledge about stem cell biology to the pathobiology of cancer, allowing the identification of CSC-restricted pathways valuable for pharmacological inhibition, and to define a fraction of cancer cells with increased resistance to chemo-radiotherapy compared to the bulk of tumor cell mass. Nevertheless, there are much controversies over the existence, origin, and nomenclature of CSCs (Lathia et al., 2011 Valent et al., 2012). The link existing between adult stem cells and CSCs has been the focus of many investigations. Although genetically engineered mouse models provided hints that GBM originates from the malignant transformation of neural stem/progenitor cells (reviewed in Lathia et al., 2011), these results should be interpreted with caution. For instance, current animal models did not exclude the possibility that also non-stem cells can give rise to GBM, when manipulated with multiple and sequential mutational hits. Consistent with this, recent studies demonstrating that GBM can be generated by cells that do not reside within neurogenic niches (Zhu et al., 2009). Functionally, CSCs are defined as a subpopulation of tumor-initiating cells having the ability to reconstitute the cellular heterogeneity typical of the original tumor. Operatively, to define CSCs some criteria need to be fulfilled, such as expression of a repertoire of markers common to stem and progenitor cells, ability to self-renew, and capability to reproduce the parental tumor upon injection into immunocompromised mice. Although informative, the expression of a single marker cannot be considered as a general principle for defining CSCs, nor a somatic stem cell. As discussed above, CD133 expression was originally used for GBM-SCs characterization. Nevertheless, this criterion nowadays appears to be oversimplified, while the validation of novel markers and their combined use might add a further level of reliability to current isolation protocols. The ability to self-renew and to differentiate into multiple lineages is a hallmark of stem cells, enabling them to maintain tissue homeostasis and to replace senescent or dying cells. Self-renewal of adult stem cells is determined through sphere-forming ability under non-adherent culture conditions. Given the analogies supposed to exist between adult stem cells and CSCs, the same assay is used for defining putative CSCs. Even though spheroids are enriched for CSCs, one should consider that tumorsphere-formation assay does not provide an exact, nor an exclusive, measurement of self-renewal ability, since this assay evaluates further biological properties, such as adhesion independence, survival, and proliferation. Overall, the ability to recreate the original tumor upon the delivery into the murine background represents the most critical factor in defining CSCs. Furthermore, our unpublished data suggests that CSCs generates tumors maintaining the original molecular portrait of the parental neoplasia, as demonstrated by mapping pathway activation through reverse-phase phosphoprotein microarray. Finally, microarray analyses demonstrated the intrinsic heterogeneous nature of GBM. This suggests that each molecular entity might stem from a different cell of origin (Phillips et al., 2006 Verhaak et al., 2010). Overall, further preclinical investigations are needed for resolving controversies surrounding the CSC model in GBM, and for acquiring a deeper understanding of subtype-restricted molecular signals.
Ovarian cancer cells cooperate to metastasize
- In a study in mice, researchers identify a previously unknown mechanism that fuels cancer spread.
- Analyses pinpoint a specific cooperative interaction between cancer cells that enables formation of tumor metastases.
- Findings shed light on mechanisms that allow tumors to invade distant organs.
- Results can inform the design of future approaches to potentially prevent tumor spread.
Any given tumor is composed of a multitude of cell types that can each look or behave differently from its neighbors. An emerging body of research suggests that these differences can influence disease progression or the way a tumor responds to drugs.
Now, a new study by Harvard Medical School scientists shows that such cell diversity can also play a critical role in a cancer's ability to invade distant sites throughout the body, a process known as metastasis.
The research, conducted in mice and published in Nature Communications, identifies a transient, cooperative interaction between ovarian cancer cells that allows otherwise nonmetastatic tumor cells to metastasize.
The team isolated subpopulations of cells from human ovarian tumors and found that none had the ability to form metastatic tumors on its own. But when certain subpopulations commingled, a cooperative biochemical interaction between the cells acted as a switch that triggered metastasis.
The findings shed light on a novel mechanism that drives tumor spread and opens new paths of study to prevent or design targeted treatments against one of cancer's deadliest features.
"Crosstalk between otherwise innocuous cells within a tumor can play a key role in determining the metastatic capacity of a cancer," said senior study author Joan Brugge, the Louise Foote Pfeiffer Professor of Cell Biology in the Blavatnik Institute at HMS.
"This mechanism needs to be considered in efforts to identify relevant therapeutic targets for the extremely difficult challenge of blocking metastasis," said Brugge, who is also co-director of the Ludwig Center at Harvard.
As scientists work to better understand the role of cell diversity within tumors, evidence has hinted that cells can cooperate to increase rates of growth and spread. The details of how this occurs, however, had thus far remained unclear.
To investigate, Brugge and colleagues, led by first author Suha Naffar-Abu Amara, HMS research fellow in cell biology, studied the characteristics of individual and mixtures of cancer cell subpopulations taken from the same tumor.
They focused on a cell line derived from human ovarian cancer, which was known to form metastatic tumors when transplanted into mice. The team isolated numerous single cells and expanded each cell into a population of identical clones. Based on differences in cell shape and growth, they selected 11 of these populations for study.
When the team injected a mixture of all 11 clonal populations into the abdomens of mice, they observed robust growth and the formation of metastatic solid tumors on different organs as expected.
However, when each population was injected individually, only one clone, called CL31, exhibited significant growth. The rest were either stagnant, decreased in number or died off entirely.
Remarkably, none of the clones, including CL31, were capable of forming solid metastatic tumors on their own.
"All the clones except one just died when injected individually, and the only way to get metastases was to mix the populations together," Brugge said. "We had no idea we would observe what we did, and this was the phenomenon that drove us for years to better understand."
To identify how mixed cancer cells led to tumor spread whereas individual subpopulations did not, the team labeled each clone with a unique DNA barcode and looked at the composition of metastatic tumors.
Initially, all 11 clones were present in roughly the same numbers following transplantation into the mouse. But after a few weeks, more than 80 percent of cells were CL31 clones. By week 10, metastatic tumors had formed that were almost entirely composed of CL31. This finding, coupled with additional experiments, provided strong evidence that interactions between clonal populations were somehow allowing CL31 cells to become metastatic.
Genetic analyses revealed that CL31 cells exclusively possessed amplified levels of the gene ERBB2, which encodes a growth factor called HER2 that has been implicated in certain types of breast cancer. Notably, when the original tumor was genetically analyzed in bulk, the researchers saw small populations of cells with amplified ERBB2, confirming that the single-cell cloning approach successfully identified rare cells from the original tumor.
Searching for factors that activate ERBB2 in CL31 cells, the researchers homed in on a signaling protein called amphiregulin, which is found in elevated amounts in advanced ovarian cancers and has been associated with poor prognosis.
The team identified a specific clonal population that expresses high levels of amphiregulin. When injected together with CL31, the mixture of these two cell subpopulations was sufficient to cause metastases. This cooperative interaction involving amphiregulin helped CL31 invade and colonize other organs. But this teamwork was only temporary, as CL31 soon outcompeted its partner. After a few weeks, only CL31 cells remained in the tumors.
Further experiments revealed that exposure to amphiregulin for only a short window of time after injection of the CL31 is sufficient to act as a switch that allows CL31 to form metastatic tumors.
"Identifying the molecular mechanism underlying the clonal cooperation was challenging," Naffar-Abu Amara said. "Many working hypotheses arose and died, but eventually pieces of the puzzle started to fall into place. Watching the building blocks ultimately align was a very exciting and satisfying phase in our research."
The identification of this previously unknown mechanism driving metastasis now opens new lines of study to better understand the process and find new approaches to control it, the authors said.
The team conducted experiments that showed blocking the ability of CL31 cells to recognize amphiregulin could interfere with the formation of solid metastatic tumors. However, myriad questions must be answered before any potential clinical applications can be considered, according to Brugge and colleagues.
The study findings were based on cell and mouse models, and additional research is required to confirm whether the mechanism is similar in humans. Unlike most other cancers, ovarian cancer cells grow and spread in the fluid of the abdominal cavity, forming solid metastatic tumors on the surfaces of sites such as the diaphragm and pancreas. Further studies are needed to reveal if similar mechanisms play a role in cancers that spread through the blood or lymphatic systems.
The results also inform efforts to better understand the behaviors and interactions of different cell types within tumors, according to the authors. These dynamics are increasingly implicated as a cause in unpredictable drug sensitivity, drug resistance and properties such as metastasis. Ovarian cancer metastasis therefore offers an intriguing model for studying the evolutionary dynamics of cooperation among cancer cells, the authors wrote.
In addition, the study highlights the importance of animal models in the study of cancer. Typically, research on metastases involves comparisons between the primary tumor and a metastatic tumor, which can omit information about time-sensitive interactions.
"Because this interaction was transient, standard approaches of comparing primary and metastatic tumors are not feasible," Brugge said. "We would be blind to this kind of mechanism without employing animal models and individual clonal populations of cells."
Additional authors on the study include Hendrik Kuiken, Laura Selfors, Timothy Butler, Marco Leung, Cheuk Leung, Elaine Kuhn, Teodora Kolarova, Carina Hage, Kripa Ganesh, Richard Panayiotou, Rosemary Foster, Bo Rueda, Athena Aktipis, Paul Spellman, Tan Ince, Joanne Xiu, Matthew Oberley, Zoran Gatalica, Nicholas Navin, Gordon Mills and Rodrick Bronson.
The study was supported by the National Cancer Institute (grant CA181543), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, MD Anderson (grants R50 CA221675, R33CA214310 and OC130649), the Knight Cancer Institute and the National Institute of Neurological Disorders and Stroke (grants NS072030, 5T32GM07133 and 129098-RSG-16-092-01-TBG).
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
A neoplasm can be benign, potentially malignant, or malignant (cancer). 
- include uterine fibroids, osteophytes and melanocytic nevi (skin moles). They are circumscribed and localized and do not transform into cancer. 
- Potentially-malignant neoplasms include carcinoma in situ. They are localised, do not invade and destroy but in time, may transform into a cancer.
- Malignant neoplasms are commonly called cancer. They invade and destroy the surrounding tissue, may form metastases and, if untreated or unresponsive to treatment, will generally prove fatal.
- Secondary neoplasm refers to any of a class of cancerous tumor that is either a metastatic offshoot of a primary tumor, or an apparently unrelated tumor that increases in frequency following certain cancer treatments such as chemotherapy or radiotherapy.
- Rarely there can be a metastatic neoplasm with no known site of the primary cancer and this is classed as a cancer of unknown primary origin.
Neoplastic tumors are often heterogeneous and contain more than one type of cell, but their initiation and continued growth is usually dependent on a single population of neoplastic cells. These cells are presumed to be clonal – that is, they are derived from the same cell,  and all carry the same genetic or epigenetic anomaly – evident of clonality. For lymphoid neoplasms, e.g. lymphoma and leukemia, clonality is proven by the amplification of a single rearrangement of their immunoglobulin gene (for B cell lesions) or T cell receptor gene (for T cell lesions). The demonstration of clonality is now considered to be necessary to identify a lymphoid cell proliferation as neoplastic. 
It is tempting to define neoplasms as clonal cellular proliferations but the demonstration of clonality is not always possible. Therefore, clonality is not required in the definition of neoplasia.
Neoplasm vs. tumor Edit
The word tumor or tumour comes from the Latin word for swelling, which is one of the cardinal signs of inflammation. The word originally referred to any form of swelling, neoplastic or not. In modern English, tumor is used as a synonym for neoplasm (a solid or fluid-filled cystic lesion that may or may not be formed by an abnormal growth of neoplastic cells) that appears enlarged in size.   Some neoplasms do not form a tumor - these include leukemia and most forms of carcinoma in situ. Tumor is also not synonymous with cancer. While cancer is by definition malignant, a tumor can be benign, precancerous, or malignant.
The terms mass and nodule are often used synonymously with tumor. Generally speaking, however, the term tumor is used generically, without reference to the physical size of the lesion.  More specifically, the term mass is often used when the lesion has a maximal diameter of at least 20 millimeters (mm) in greatest direction, while the term nodule is usually used when the size of the lesion is less than 20 mm in its greatest dimension (25.4 mm = 1 inch). 
Tumors in humans occur as a result of accumulated genetic and epigenetic alterations within single cells, which cause the cell to divide and expand uncontrollably.  A neoplasm can be caused by an abnormal proliferation of tissues, which can be caused by genetic mutations. Not all types of neoplasms cause a tumorous overgrowth of tissue, however (such as leukemia or carcinoma in situ) and similarities between neoplasmic growths and regenerative processes, e.g., dedifferentiation and rapid cell proliferation, have been pointed out. 
Tumor growth has been studied using mathematics and continuum mechanics. Vascular tumors such as hemangiomas and lymphangiomas (formed from blood or lymph vessels) are thus looked at as being amalgams of a solid skeleton formed by sticky cells and an organic liquid filling the spaces in which cells can grow.  Under this type of model, mechanical stresses and strains can be dealt with and their influence on the growth of the tumor and the surrounding tissue and vasculature elucidated. Recent findings from experiments that use this model show that active growth of the tumor is restricted to the outer edges of the tumor and that stiffening of the underlying normal tissue inhibits tumor growth as well. 
Benign conditions that are not associated with an abnormal proliferation of tissue (such as sebaceous cysts) can also present as tumors, however, but have no malignant potential. Breast cysts (as occur commonly during pregnancy and at other times) are another example, as are other encapsulated glandular swellings (thyroid, adrenal gland, pancreas).
Encapsulated hematomas, encapsulated necrotic tissue (from an insect bite, foreign body, or other noxious mechanism), keloids (discrete overgrowths of scar tissue) and granulomas may also present as tumors.
Discrete localized enlargements of normal structures (ureters, blood vessels, intrahepatic or extrahepatic biliary ducts, pulmonary inclusions, or gastrointestinal duplications) due to outflow obstructions or narrowings, or abnormal connections, may also present as a tumor. Examples are arteriovenous fistulae or aneurysms (with or without thrombosis), biliary fistulae or aneurysms, sclerosing cholangitis, cysticercosis or hydatid cysts, intestinal duplications, and pulmonary inclusions as seen with cystic fibrosis. It can be dangerous to biopsy a number of types of tumor in which the leakage of their contents would potentially be catastrophic. When such types of tumors are encountered, diagnostic modalities such as ultrasound, CT scans, MRI, angiograms, and nuclear medicine scans are employed prior to (or during) biopsy or surgical exploration/excision in an attempt to avoid such severe complications.
DNA damage Edit
DNA damage is considered to be the primary underlying cause of malignant neoplasms known as cancers.  Its central role in progression to cancer is illustrated in the figure in this section, in the box near the top. (The central features of DNA damage, epigenetic alterations and deficient DNA repair in progression to cancer are shown in red.) DNA damage is very common. Naturally occurring DNA damages (mostly due to cellular metabolism and the properties of DNA in water at body temperatures) occur at a rate of more than 60,000 new damages, on average, per human cell, per day [ citation needed ] [also see article DNA damage (naturally occurring) ]. Additional DNA damages can arise from exposure to exogenous agents. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking.  UV light from solar radiation causes DNA damage that is important in melanoma.  Helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer.  Bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.  Katsurano et al. indicated that macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis.  [ unreliable source? ] Some sources of DNA damage are indicated in the boxes at the top of the figure in this section.
Individuals with a germ line mutation causing deficiency in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer. Some germ line mutations in DNA repair genes cause up to 100% lifetime chance of cancer (e.g., p53 mutations).  These germ line mutations are indicated in a box at the left of the figure with an arrow indicating their contribution to DNA repair deficiency.
About 70% of malignant neoplasms have no hereditary component and are called "sporadic cancers".  Only a minority of sporadic cancers have a deficiency in DNA repair due to mutation in a DNA repair gene. However, a majority of sporadic cancers have deficiency in DNA repair due to epigenetic alterations that reduce or silence DNA repair gene expression. For example, of 113 sequential colorectal cancers, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).  Five reports present evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.     
Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).  In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1. 
In further examples, epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.  Epigenetic alterations causing reduced expression of DNA repair genes is shown in a central box at the third level from the top of the figure in this section, and the consequent DNA repair deficiency is shown at the fourth level.
When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair   or in homologous recombinational repair (HRR). 
During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.   DNA repair deficiencies (level 4 in the figure) cause increased DNA damages (level 5 in the figure) which result in increased somatic mutations and epigenetic alterations (level 6 in the figure).
Field defects, normal appearing tissue with multiple alterations (and discussed in the section below), are common precursors to development of the disordered and improperly proliferating clone of tissue in a malignant neoplasm. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations.
Once a cancer is formed, it usually has genome instability. This instability is likely due to reduced DNA repair or excessive DNA damage. Because of such instability, the cancer continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, demonstrating tumor heterogeneity (i.e. present in all areas of the cancer), 59 mutations shared by some (but not all areas), and 29 “private” mutations only present in one of the areas of the cancer. 
Field defects Edit
Various other terms have been used to describe this phenomenon, including "field effect", "field cancerization", and "field carcinogenesis". The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer.  Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise.
Field defects are important in progression to cancer.   However, in most cancer research, as pointed out by Rubin  “The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion.  Similarly, Vogelstein et al.  point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.
An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also influences of exogenous environmental factors and molecular changes in the local microenvironment on neoplastic evolution from tumor initiation to patient death. 
In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. Thus, a patch of abnormal tissue may arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo, there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer).
In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated, in the diagram below the photo, by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon.
If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm.
In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.
|Cancer||Gene||Frequency in Cancer||Frequency in Field Defect||Ref.|
|Head and Neck||MGMT||54%||38%|||
|Head and Neck||MLH1||33%||25%|||
|Head and Neck||MLH1||31%||20%|||
Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size. 
Genome instability Edit
Cancers are known to exhibit genome instability or a mutator phenotype.  The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA.  Within this protein-coding DNA (called the exome), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be “driver” mutations, and the remaining ones may be “passenger” mutations  However, the average number of DNA sequence mutations in the entire genome (including non-protein-coding regions) within a breast cancer tissue sample is about 20,000.  In an average melanoma tissue sample (where melanomas have a higher exome mutation frequency  ) the total number of DNA sequence mutations is about 80,000.  This compares to the very low mutation frequency of about 70 new mutations in the entire genome between generations (parent to child) in humans.  
The high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defects giving rise to a cancer (e.g. yellow area in the diagram in this section) is a deficiency in DNA repair. The large field defects surrounding colon cancers (extending to at about 10 cm on each side of a cancer) were shown by Facista et al.  to frequently have epigenetic defects in 2 or 3 DNA repair proteins (ERCC1, XPF or PMS2) in the entire area of the field defect. Deficiencies in DNA repair cause increased mutation rates.    A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cells acquire additional mutations/epimutations that do provide a proliferative advantage.
The term neoplasm is a synonym of tumor. Neoplasia denotes the process of the formation of neoplasms/tumors, and the process is referred to as a neoplastic process. The word neoplastic itself comes from Greek neo 'new' and plastic 'formed, molded'.
The term tumor derives from the Latin noun tumor 'a swelling', ultimately from the verb tumēre 'to swell'. In the British Commonwealth, the spelling tumour is commonly used, whereas in the U.S. the word is usually spelled tumor.
In its medical sense, tumor has traditionally meant an abnormal swelling of the flesh. The Roman medical encyclopedist Celsus (c. 30 BC–38 AD) described the four cardinal signs of acute inflammation as tumor, dolor, calor, and rubor (swelling, pain, increased heat, and redness). (His treatise, De Medicina, was the first medical book printed in 1478 following the invention of the movable-type printing press.)
In contemporary English, the word tumor is often used as a synonym for a cystic (liquid-filled) growth or solid neoplasm (cancerous or non-cancerous),  with other forms of swelling often referred to as "swellings". 
Related terms occur commonly in the medical literature, where the nouns tumefaction and tumescence (derived from the adjective tumescent),  are current medical terms for non-neoplastic swelling. This type of swelling is most often caused by inflammation caused by trauma, infection, and other factors.
Tumors may be caused by conditions other than an overgrowth of neoplastic cells, however. Cysts (such as sebaceous cysts) are also referred to as tumors, even though they have no neoplastic cells. This is standard in medical-billing terminology (especially when billing for a growth whose pathology has yet to be determined).
Treatment of Recurrent Childhood High-Grade Astrocytomas
For information about the treatments listed below, see the Treatment Option Overview section.
When high-grade astrocytoma recurs after treatment, it usually comes back where the tumor first formed. Before more cancer treatment is given, imaging tests, biopsy, or surgery are done to find out if there is cancer and how much there is.
Treatment of recurrent childhood high-grade astrocytoma may include the following:
- Surgery to remove the tumor. with stem cell transplant. . with a BRAF inhibitor (vemurafenib or dabrafenib).
- A clinical trial of immunotherapy with an immune checkpoint inhibitor.
- A clinical trial that checks a sample of the patient's tumor for certain gene changes. The type of targeted therapy that will be given to the patient depends on the type of gene change.
- A clinical trial of targeted therapy with a combination of BRAF inhibitors (dabrafenib and trametinib) in patients with mutations in the BRAF gene.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
A cancer mystery more than 40 years old is solved thanks to epigenetics
Credit: CC0 Public Domain
Before the first oncogene mutations were discovered in human cancer in the early 1980s, the 1970s provided the first data suggesting alterations in the genetic material of tumors. In this context, the prestigious journal Nature published in 1975 the existence of a specific alteration in the transformed cell: an RNA responsible for carrying an amino acid to build proteins (transfer RNA) was missing a piece, the enigmatic nucleotide 'Y.'
After that outstanding observation, virtually no developments were made for forty-five years on the causes and consequences of not having the correct base in RNA.
In an article published in Proceedings of the National Academy of Sciences (PNAS) by the group of Dr. Manel Esteller, Director of the Josep Carreras Leukaemia Research Institute, ICREA Research Professor and Professor of Genetics at the University of Barcelona has solved this mystery by observing that in cancer cells the protein that generates the nucleotide Y is epigenetically inactivated, causing small but highly aggressive tumors.
"Since the original discovery in 1975, there has been much biochemical work to characterize the enzymes involved in the different steps that lead to the desired nucleotide Y, a hypermodified guanine, but without connecting this characterization with its defect in tumor biology. We have built the bridge between these two worlds by demonstrating that the epigenetic silencing of the TYW2 gene is the cause of the loss of the elusive nucleotide Y," explains Dr. Esteller about the article in PNAS
Esteller adds, "Epigenetic blockade of the TYW2 gene occurs mainly in colon, stomach and uterine cancer. And it has undesirable consequences for healthy cells: the postman (RNA) that sends the signal to produce the bricks of our body (proteins) begins to accumulate errors and the cell takes on a different appearance, far from the normal epithelium, which we call mesenchymal and which it is associated with the appearance of metastasis."
"In this regard, when we study patients with colon cancer in early stages, the epigenetic defect of TYW2 and the loss of the nucleotide Y is associated with those tumors that, although small in size, already lead to decreased survival of that person. We would like to explore now how to restore the activity of the TYW2 gene and restore the necessary Y component in order to close the cycle of this story that began so brilliantly in 1975, at the dawn of modern molecular biology," concludes Esteller.
Women with LCIS have about a 7 to 12 times higher risk of developing invasive cancer in either breast. For this reason, women with LCIS should make sure they have regular breast cancer screening tests and follow-up visits with a health care provider for the rest of their lives.
Having LCIS does increase your risk of developing invasive breast cancer later on. But since LCIS is not a true cancer or pre-cancer, often no treatment is needed after the biopsy.
Sometimes if LCIS is found using a needle biopsy, the doctor might recommend that it be removed completely (with an excisional biopsy or some other type of breast-conserving surgery) to help make sure that LCIS was the only abnormality there. This is especially true if the LCIS is described as pleomorphic (meaning the cells look more abnormal) or if it has necrosis (areas of dead cells), in which case it might be more likely to grow quickly.
Even after an excisional biopsy, if pleomorphic LCIS is found, some doctors might recommend another surgery to make sure it has all been removed. This is because this type of LCIS may be more likely to turn into invasive cancer.