Cancer is fundamentally a disease of tissue growth regulation. In order for a normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered.
The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal cell into a cancer cell.
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia and results in the production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from the integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants.
Replication of the data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention are built into the process and safeguard the cell against cancer. If a significant error occurs, the damaged cell can self-destruct through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called Carcinogens, repeated physical injury, heat, ionizing radiation, or hypoxia.
The errors that cause cancer are self-amplifying and compounding, for example:
Characteristic abilities developed by cancers are divided into categories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism, and evasion of immune destruction.
The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal cell into a cancer cell.
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.
Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia and results in the production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from the integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants.
Replication of the data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention are built into the process and safeguard the cell against cancer. If a significant error occurs, the damaged cell can self-destruct through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called Carcinogens, repeated physical injury, heat, ionizing radiation, or hypoxia.
The errors that cause cancer are self-amplifying and compounding, for example:
- A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
- A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
- A further mutation may cause the loss of a tumor suppressor gene, disrupting the apoptosis signaling pathway and immortalizing the cell.
- A further mutation in the signaling machinery of the cell might send error-causing signals to nearby cells.
Characteristic abilities developed by cancers are divided into categories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism, and evasion of immune destruction.
Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these leads to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, (contrast) CT scans, and endoscopy.
The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological grade, genetic abnormalities, and other features. Together, this information is useful to evaluate the prognosis and to choose the best treatment.
Cytogenetics and immunohistochemistry are other types of tissue tests. These tests provide information about molecular changes (such as mutations, fusion genes, and numerical chromosome changes) and may thus also indicate the prognosis and best treatment.
Cancer diagnosis can cause psychological distress and psychosocial interventions, such as talking therapy, may help people with this.
The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological grade, genetic abnormalities, and other features. Together, this information is useful to evaluate the prognosis and to choose the best treatment.
Cytogenetics and immunohistochemistry are other types of tissue tests. These tests provide information about molecular changes (such as mutations, fusion genes, and numerical chromosome changes) and may thus also indicate the prognosis and best treatment.
Cancer diagnosis can cause psychological distress and psychosocial interventions, such as talking therapy, may help people with this.
Although many diseases (such as heart failure) may have a worse prognosis than most cases of cancer, cancer is the subject of widespread fear and taboos. The euphemism of "a long illness" to describe cancers leading to death is still commonly used in obituaries, rather than naming the disease explicitly, reflecting an apparent stigma. Cancer is also euphemized as "the C-word"; Macmillan Cancer Support uses the term to try to lessen the fear around the disease. In Nigeria, one local name for cancer translates into English as "the disease that cannot be cured". This deep belief that cancer is necessarily a difficult and usually deadly disease is reflected in the systems chosen by society to compile cancer statistics: the most common form of cancer—non-melanoma skin cancers, accounting for about one-third of cancer cases worldwide, but very few deaths—are excluded from cancer statistics specifically because they are easily treated and almost always cured, often in a single, short, outpatient procedure.
Western conceptions of patients' rights for people with cancer include a duty to fully disclose the medical situation to the person, and the right to engage in shared decision-making in a way that respects the person's own values. In other cultures, other rights and values are preferred. For example, most African cultures value whole families rather than individualism. In parts of Africa, a diagnosis is commonly made so late that a cure is not possible, and treatment, if available at all, would quickly bankrupt the family. As a result of these factors, African healthcare providers tend to let family members decide whether, when, and how to disclose the diagnosis, and they tend to do so slowly and circuitously, as the person shows interest and an ability to cope with the grim news. People from Asian and South American countries also tend to prefer a slower, less candid approach to disclosure than is idealized in the United States and Western Europe, and they believe that sometimes it would be preferable not to be told about a cancer diagnosis. In general, disclosure of the diagnosis is more common than it was in the 20th century, but full disclosure of the prognosis is not offered to many patients around the world.
In the United States and some other cultures, cancer is regarded as a disease that must be "fought" to end the "civil insurrection"; a War on Cancer was declared in the US. Military metaphors are particularly common in descriptions of cancer's human effects, and they emphasize both the state of the patient's health and the need to take immediate, decisive actions himself rather than to delay, ignore, or rely entirely on others. The military metaphors also help rationalize radical, destructive treatments.
In the 1970s, a relatively popular alternative cancer treatment in the US was a specialized form of talk therapy, based on the idea that cancer was caused by a bad attitude. People with a "cancer personality"—depressed, repressed, self-loathing, and afraid to express their emotions—were believed to have manifested cancer through subconscious desire. Some psychotherapists said that treatment to change the patient's outlook on life would cure the cancer. Among other effects, this belief allowed society to blame the victim for having caused cancer (by "wanting" it) or having prevented its cure (by not becoming a sufficiently happy, fearless, and loving person). It also increased patients' anxiety, as they incorrectly believed that natural emotions of sadness, anger, or fear shorten their lives. The idea was ridiculed by Susan Sontag, who published Illness as Metaphor while recovering from treatment for breast cancer in 1978. Although the original idea is now generally regarded as nonsense, the idea partly persists in a reduced form with a widespread, but incorrect, belief that deliberately cultivating a habit of positive thinking will increase survival. This notion is particularly strong in breast cancer culture.
In the United States and some other cultures, cancer is regarded as a disease that must be "fought" to end the "civil insurrection"; a War on Cancer was declared in the US. Military metaphors are particularly common in descriptions of cancer's human effects, and they emphasize both the state of the patient's health and the need to take immediate, decisive actions himself rather than to delay, ignore, or rely entirely on others. The military metaphors also help rationalize radical, destructive treatments.
In the 1970s, a relatively popular alternative cancer treatment in the US was a specialized form of talk therapy, based on the idea that cancer was caused by a bad attitude. People with a "cancer personality"—depressed, repressed, self-loathing, and afraid to express their emotions—were believed to have manifested cancer through subconscious desire. Some psychotherapists said that treatment to change the patient's outlook on life would cure the cancer. Among other effects, this belief allowed society to blame the victim for having caused cancer (by "wanting" it) or having prevented its cure (by not becoming a sufficiently happy, fearless, and loving person). It also increased patients' anxiety, as they incorrectly believed that natural emotions of sadness, anger, or fear shorten their lives. The idea was ridiculed by Susan Sontag, who published Illness as Metaphor while recovering from treatment for breast cancer in 1978. Although the original idea is now generally regarded as nonsense, the idea partly persists in a reduced form with a widespread, but incorrect, belief that deliberately cultivating a habit of positive thinking will increase survival. This notion is particularly strong in breast cancer culture.
One idea about why people with cancer are blamed or stigmatized called the just-world hypothesis, is that blaming cancer on the patient's actions or attitudes allows the blamers to regain a sense of control. This is based upon the blamers' belief that the world is fundamentally just and so any dangerous illness, like cancer, must be a type of punishment for bad choices because in a just world, bad things would not happen to good people.
The total healthcare expenditure on cancer in the US was estimated to be $80.2 billion in 2015. Even though cancer-related health care expenditures have increased in absolute terms during recent decades, the share of health expenditure devoted to cancer treatment has remained close to 5% between the 1960s and 2004. A similar pattern has been observed in Europe where about 6% of all health care expenditures are spent on cancer treatment.
In addition to health care expenditure and financial toxicity, cancer causes indirect costs in the form of productivity losses due to sick days, permanent incapacity and disability as well as premature death during working age. Cancer causes also costs for informal care.
Indirect costs and informal care costs are typically estimated to exceed or equal the health care costs of cancer.
The total healthcare expenditure on cancer in the US was estimated to be $80.2 billion in 2015. Even though cancer-related health care expenditures have increased in absolute terms during recent decades, the share of health expenditure devoted to cancer treatment has remained close to 5% between the 1960s and 2004. A similar pattern has been observed in Europe where about 6% of all health care expenditures are spent on cancer treatment.
In addition to health care expenditure and financial toxicity, cancer causes indirect costs in the form of productivity losses due to sick days, permanent incapacity and disability as well as premature death during working age. Cancer causes also costs for informal care.
Indirect costs and informal care costs are typically estimated to exceed or equal the health care costs of cancer.
In the United States, cancer is included as a protected condition by the Equal Employment Opportunity Commission (EEOC), mainly due to the potential for cancer to have discriminating effects on workers. Discrimination in the workplace could occur if an employer holds a false belief that a person with cancer is not capable of doing a job properly and may ask for more sick leave than other employees. Employers may also make hiring or firing decisions based on misconceptions about cancer disabilities, if present. The EEOC provides interview guidelines for employers, as well as lists of possible solutions for assessing and accommodating employees with cancer.
Because cancer is a class of diseases, it is unlikely that there will ever be a single "cure for cancer" any more than there will be a single treatment for all infectious diseases. Angiogenesis inhibitors were once incorrectly thought to have the potential as a "silver bullet" treatment applicable to many types of cancer. Angiogenesis inhibitors and other cancer therapeutics are used in combination to reduce cancer morbidity and mortality.
Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment. Treatments that succeeded in one cancer type can be tested against other types. Diagnostic tests are under development to better target the right therapies to the right patients, based on their individual biology.
Cancer research focuses on the following issues:
Competition for financial resources appears to have suppressed the creativity, cooperation, risk-taking, and original thinking required to make fundamental discoveries, unduly favoring low-risk research into small incremental advancements over riskier, more innovative research. Other consequences of competition appear to be many studies with dramatic claims whose results cannot be replicated and perverse incentives that encourage grantee institutions to grow without making sufficient investments in their own faculty and facilities.
Virotherapy, which uses converting viruses, is being studied.
In the wake of the COVID-19 pandemic, there has been a worry that cancer research and treatment are slowing down.
Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment. Treatments that succeeded in one cancer type can be tested against other types. Diagnostic tests are under development to better target the right therapies to the right patients, based on their individual biology.
Cancer research focuses on the following issues:
- Agents (e.g. viruses) and events (e.g. mutations) that cause or facilitate genetic changes in cells destined to become cancer.
- The precise nature of the genetic damage and the genes that are affected by it.
- The consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell and in facilitating additional genetic events that lead to further progression of cancer.
Competition for financial resources appears to have suppressed the creativity, cooperation, risk-taking, and original thinking required to make fundamental discoveries, unduly favoring low-risk research into small incremental advancements over riskier, more innovative research. Other consequences of competition appear to be many studies with dramatic claims whose results cannot be replicated and perverse incentives that encourage grantee institutions to grow without making sufficient investments in their own faculty and facilities.
Virotherapy, which uses converting viruses, is being studied.
In the wake of the COVID-19 pandemic, there has been a worry that cancer research and treatment are slowing down.
Terror management theory maintains that people suffer cognitive dissonance (anxiety) when they are reminded of their inevitable death. Through terror management, individuals are motivated to seek consonant elements – symbols that make sense of mortality and death in satisfactory ways (i.e. boosting self-esteem).
Research has found that strong belief in religious or secular meaning systems affords psychological security and hope. It is moderates (e.g. agnostics, slightly religious individuals) who likely suffer the most anxiety from their meaning systems. Religious meaning systems are specially adapted to manage death anxiety because they are unlikely to be disconfirmed (for various reasons), they are all-encompassing, and they promise literal immortality.
Research has found that strong belief in religious or secular meaning systems affords psychological security and hope. It is moderates (e.g. agnostics, slightly religious individuals) who likely suffer the most anxiety from their meaning systems. Religious meaning systems are specially adapted to manage death anxiety because they are unlikely to be disconfirmed (for various reasons), they are all-encompassing, and they promise literal immortality.
Cancer affects approximately 1 in 1,000 pregnant women. The most common cancers found during pregnancy are the same as the most common cancers found in non-pregnant women during childbearing ages: breast cancer, cervical cancer, leukemia, lymphoma, melanoma, ovarian cancer, and colorectal cancer.
Diagnosing new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed to be a normal discomfort associated with pregnancy. As a result, cancer is typically discovered at a somewhat later stage than average. Some imaging procedures, such as MRIs (magnetic resonance imaging), CT scans, ultrasounds, and mammograms with fetal shielding are considered safe during pregnancy; some others, such as PET scans, are not.
Treatment is generally the same as for non-pregnant women. However, radiation and radioactive drugs are normally avoided during pregnancy, especially if the fetal dose might exceed 100 c Gy. In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed late in the pregnancy. Early deliveries are often used to advance the start of treatment. Surgery is generally safe, but pelvic surgeries during the first trimester may cause miscarriage. Some treatments, especially certain chemotherapy drugs given during the first trimester, increase the risk of birth defects and pregnancy loss (spontaneous abortions and stillbirths).
Elective abortions are not required and, for the most common forms and stages of cancer, do not improve the mother's survival. In a few instances, such as advanced uterine cancer, the pregnancy cannot be continued and in others, the patient may end the pregnancy so that she can begin aggressive chemotherapy.
Some treatments can interfere with the mother's ability to give birth vaginally or to breastfeed. Cervical cancer may require birth by Caesarean section. Radiation to the breast reduces the ability of that breast to produce milk and increases the risk of mastitis. Also, when chemotherapy is given after birth, many of the drugs appear in breast milk, which could harm the baby.
Diagnosing new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed to be a normal discomfort associated with pregnancy. As a result, cancer is typically discovered at a somewhat later stage than average. Some imaging procedures, such as MRIs (magnetic resonance imaging), CT scans, ultrasounds, and mammograms with fetal shielding are considered safe during pregnancy; some others, such as PET scans, are not.
Treatment is generally the same as for non-pregnant women. However, radiation and radioactive drugs are normally avoided during pregnancy, especially if the fetal dose might exceed 100 c Gy. In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed late in the pregnancy. Early deliveries are often used to advance the start of treatment. Surgery is generally safe, but pelvic surgeries during the first trimester may cause miscarriage. Some treatments, especially certain chemotherapy drugs given during the first trimester, increase the risk of birth defects and pregnancy loss (spontaneous abortions and stillbirths).
Elective abortions are not required and, for the most common forms and stages of cancer, do not improve the mother's survival. In a few instances, such as advanced uterine cancer, the pregnancy cannot be continued and in others, the patient may end the pregnancy so that she can begin aggressive chemotherapy.
Some treatments can interfere with the mother's ability to give birth vaginally or to breastfeed. Cervical cancer may require birth by Caesarean section. Radiation to the breast reduces the ability of that breast to produce milk and increases the risk of mastitis. Also, when chemotherapy is given after birth, many of the drugs appear in breast milk, which could harm the baby.
For many years, our research team has studied the features of breast cancer progression depending on intra-tumoral heterogeneity. Particular attention has been paid to the phenotypic diversity of the primary tumor in invasive carcinoma of no special type, which accounts for the bulk (80%) of all histological types of breast cancer.
Despite the considerable structural diversity of the primary breast tumor, five main types of morphological structures can be distinguished: alveolar, trabecular, tubular and solid structures, and discrete groups of tumor cells (Fig. 2). The alveolar structures are tumor cell clusters of round or slightly irregular shape. The morphology of the cells that form this type of structure varies from small cells with moderate cytoplasm and round nuclei to large cells with hyperchromatic nuclei of irregular shape and moderate cytoplasm. The trabecular structures are either short, linear associations formed by a single row of small, rather monomorphic cells or wide cell clusters consisting of two rows of medium-sized cells with moderate cytoplasm and round normochromic or hyperchromatic nuclei. The tubular structures are formed by single or two rows of rather monomorphic cells with round normochromic nuclei. The solid structures are fields of various sizes and shapes, consisting of either small cells with moderate cytoplasm and monomorphic nuclei or large cells with abundant cytoplasm and polymorphic nuclei. Discrete groups of cells occur in the form of clusters of one to four cells with variable morphologies.
Despite the considerable structural diversity of the primary breast tumor, five main types of morphological structures can be distinguished: alveolar, trabecular, tubular and solid structures, and discrete groups of tumor cells (Fig. 2). The alveolar structures are tumor cell clusters of round or slightly irregular shape. The morphology of the cells that form this type of structure varies from small cells with moderate cytoplasm and round nuclei to large cells with hyperchromatic nuclei of irregular shape and moderate cytoplasm. The trabecular structures are either short, linear associations formed by a single row of small, rather monomorphic cells or wide cell clusters consisting of two rows of medium-sized cells with moderate cytoplasm and round normochromic or hyperchromatic nuclei. The tubular structures are formed by single or two rows of rather monomorphic cells with round normochromic nuclei. The solid structures are fields of various sizes and shapes, consisting of either small cells with moderate cytoplasm and monomorphic nuclei or large cells with abundant cytoplasm and polymorphic nuclei. Discrete groups of cells occur in the form of clusters of one to four cells with variable morphologies.
According to the data accumulated to date, it may be assumed that different morphological structures of breast tumors correspond to certain types of invasions. Therefore, alveolar, trabecular, and solid structures that are characterized by the presence of cell-cell contacts may be referred to as morphological manifestations of collective migration, while discrete groups of tumor cells may be referred to as manifestations of individual migration. Interestingly, the first batch of data obtained in a study of the expression of cell adhesion genes fully confirms this hypothesis. For example, there was a decrease in the activity of the genes of cadherins, which are responsible for cell-cell contacts, in the order: solid – alveolar and trabecular structures – discrete groups of tumor cells. In this case, the number of expressed genes of integrins involved in the adhesion of tumor cells to the extracellular matrix was reduced in the order: solid and alveolar – trabecular structures – discrete groups of tumor cells.
For cancer, invasion is the direct extension and penetration by cancer cells into neighboring tissues. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to more distant locations. Yet, lymphovascular invasion is generally the first step of metastasis.
Numerous studies have confirmed the existence of two main patterns of cancer cell invasion by cell migration: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid-mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumorally morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.
The results of numerous experimental and clinical studies of malignant neoplasms have indicated that invasive growth and metastasis are the main manifestations of tumor progression, which represent two closely related processes.
For cancer, invasion is the direct extension and penetration by cancer cells into neighboring tissues. It is generally distinguished from metastasis, which is the spread of cancer cells through the circulatory system or the lymphatic system to more distant locations. Yet, lymphovascular invasion is generally the first step of metastasis.
Numerous studies have confirmed the existence of two main patterns of cancer cell invasion by cell migration: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid-mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumorally morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.
The results of numerous experimental and clinical studies of malignant neoplasms have indicated that invasive growth and metastasis are the main manifestations of tumor progression, which represent two closely related processes.
A malignant tumor is characterized by the possibility to implement such a biological phenomenon as the metastatic cascade which is a unique multi-stage “program” where cell invasion is a trigger and a key factor for further cancer progression and metastasis in distant organs and tissues. Massive metastatic lesions lead to the development of severe organ failure and, therefore, a patient’s death. The range between “end” points of a complex invasive metastatic process –the invasion of the primary tumor into surrounding tissues and the formation of metastatic foci –comprises several stages, the passage of which is strictly necessary for the successful development and subsequent progression of tumor growth: intravasation, survival, and presence in the systemic circulation, extravasation with subsequent colonization of organs by tumor cells, and the formation of clinically detectable metastasis. Tumor growth is accompanied by increasing pressure on extracellular matrix structures, whereas the tissue microenvironment fights to retain its functional-anatomic integrity via increasing pressure on tumor cells. The factors limiting the growth of malignant neoplasm include the basal membrane and various components of the surrounding stroma, increased interstitial pressure, limited oxygen supply to tumor cells and the formation of active oxygen forms, hypoxia conditions, and permanent exposure to immune system cells. Given the intratumoral heterogeneity, in the struggle for survival, some tumor cells may be subjected to regression and death, while other cells, which resist powerful, counteracting microenvironmental factors, gain an aggressive phenotype and the ability of metastatic progression. Invasive tumor growth is enabled by the detachment of malignant cells from the tumor mass due to a reduction in or complete loss of intercellular adhesion molecules, and, therefore, the cells gain the ability of anomalously high motility enabling penetration through the stiff structural elements of the surrounding stroma. In this case, the invasion process extensively involves various molecular and cellular mechanisms that, according to published data, depend directly on another biological phenomenon – the epithelial-mesenchymal transformation, which was first described by E.D. Hay in 1995. Later, the term “epithelial-mesenchymal transition” (EMT) was put to use to clarify the reversibility of this process. Currently, EMT is known to underlie the processes of embryogenesis and inflammation, and regeneration of tissues and, certainly, plays a key role in the mechanisms of carcinogenesis.
Tumor cells spreading into the surrounding tissues and distant organs are known to reproduce the mechanisms and migration types characteristic of normal, non-tumor cells during physiological processes. Tumor cells, similar to normal cells, are capable of activating these mechanisms for changing their own shape, creating conditions for moving, as well as remodeling surrounding tissues to form migration pathways. The main problem is that tumor cells, in contrast to normal cells, do not have physiological “stop signals” to terminate these processes. Most likely, this leads to the establishment of migration mechanisms and promotes the progression and spread of the tumor.
Malignant cells were found to use built-in genetic programs to implement the processes that determine invasive growth and the possibility of metastasis. For example, the movement of a single cell is observed during embryonic development and inflammation (e.g., leukocyte migration). A similar mechanism of dissemination is typical of cancer cells during tumor progression and metastasis.
Along with single-cell migration, collective cell migration can occur when groups of firmly interconnected tumor cells are migrating. This type of migration indicates tissue rearrangement, underlies the processes of embryonic morphogenesis, and also is an essential component in the healing of wound surfaces.
Therefore, the key is that malignant tumor cells extensively use the mechanisms of both collective and single-cell migration as physiological prototypes in the process of invasive growth and metastasis.
Malignant cells were found to use built-in genetic programs to implement the processes that determine invasive growth and the possibility of metastasis. For example, the movement of a single cell is observed during embryonic development and inflammation (e.g., leukocyte migration). A similar mechanism of dissemination is typical of cancer cells during tumor progression and metastasis.
Along with single-cell migration, collective cell migration can occur when groups of firmly interconnected tumor cells are migrating. This type of migration indicates tissue rearrangement, underlies the processes of embryonic morphogenesis, and also is an essential component in the healing of wound surfaces.
Therefore, the key is that malignant tumor cells extensively use the mechanisms of both collective and single-cell migration as physiological prototypes in the process of invasive growth and metastasis.
At present, based on a complex of certain morphological and molecular genetic parameters, two fundamentally different patterns of invasive growth are distinguished: collective (group) cell migration and single cell migration (individual migration: Fig. 1). In this case, the migration type is largely determined by tissue microenvironment features and depends on molecular changes in tumor cells.
Determination of the invasion mechanism used by single migrating cells during migration is a complex task. Unfortunately, studies examining this issue at the molecular and morphological levels are few in numbers and mostly were carried out in vitro using specific cell lines.
However, now, there is considerable increase in the number of studies that demonstrate increasing interest in research into the molecular genetic features of tumor cells that determine the main differences between the mesenchymal and amoeboid types of cell movement during individual migration, as well as collective migration.
However, now, there is considerable increase in the number of studies that demonstrate increasing interest in research into the molecular genetic features of tumor cells that determine the main differences between the mesenchymal and amoeboid types of cell movement during individual migration, as well as collective migration.