1. Cancer Biology: Tumorigenesis Experimental models of tumorigenesis suggest that tumor development begins with initial genetic changes to the cell, such as the loss of pRb function or overexpression of c-myc. This initial cell change results in cell proliferation and increase in apoptosic cell death. A secondary genetic change, such as dysfunction of p53 or bcl-2 overexpression, then inhibits the cell death response, allowing for a significant increase in the number of cells. Subsequent genetic changes allow for further alterations in phenotype, such as invasiveness or metastasis.
2. Cancer Biology: Emergence of Tumor Cell Heterogeneity The heterogeneity of tumor-cell populations, including primary neoplasms and metastases, is well recognized. The development of biological diversity within a clonal population derived from a single transformed cell is a reflection of genetic and epigenetic instability in the cell line. Metastases from a primary neoplasm can further drive tumor evolution and progression so that most neoplastic diseases comprise multiple subpopulations of tumor cells by the time of diagnosis.
3. Cancer Biology: Host Influences on Metastatic Disease Metastatic growth can be influenced positively or negatively by several factors relating to the host environment. Anatomical factors, such as proximity of growing tumors to adjacent organs or tissues, efferent venous circulation, or lymphatic drainage paths, can facilitate the spread of metastatic disease. However, patterns of distant metastases, such as with breast cancer metastases to the ovaries, underscore the importance of the organ microenvironment in supporting or suppressing metastatic growth. The presence of angiogenic factors, such as fibroblast growth factor or interleukin 8, in certain organs, for example, can facilitate tumor vascularization and, hence, continued growth of metastases. The host immune response to the antigenic heterogeneity of the primary tumor and metastases plays a major role in determining which tumor cells are recognized and destroyed and which cells may not be recognized and, thus, allowed to grow.
4. Cancer Biology: Cancer Cells vs Normal Cells Cancer cells can be distinguished from normal cells on a number of morphological, behavioral, and genetic characteristics. Under light microscopy, cancer cells appear heterogeneous and undergo frequent mitoses. The loss of contact inhibition that can be seen in vitro is associated with increased secretion of growth factors, increased expression of oncogenes, and the loss of expression of tumor suppressor genes. In contrast, oncogene expression is rare in normal cells, which demonstrate intermittent or co-coordinated secretion of growth factors in the presence of tumor suppressor genes. Malignant cells also have a high degree of neovascularization.
5. Cancer Biology: Precancerous Conditions There are a number of precancerous conditions that involve significant cytologic changes that are premalignant, but which may either become malignant or be a risk factor for the development of future malignancies. These include benign neoplasms, polyps, and carcinoma in situ .
6. Cancer Biology: The Role of Oncogenes Oncogenes are normally dormant throughout life, but can become activated by carcinogenic effects on cellular DNA to play major roles in the process of malignant transformation. Once activated, oncogenes can produce a number of effects, including increasing the rate of synthesis of growth factors and growth-factor receptors. Release of autocrine or paracrine growth factors by tumor cells can further stimulate the growth and doubling of cells, and increased expression of growth-factor receptors can serve to coordinate these changes among tumor cells.
7. Cancer Biology: Pathogenesis A series of complex, interdependent, and interactive steps must take place before a single tumor cell evolves into cancer metastasis. Following neoplastic transformation, the proliferation of cancer cells must first be supported by the host organ. In order for the tumor mass to exceed 1 to 2 mm in diameter, angiogenesis must take place. Some tumor cells develop motility and are then able to invade the host stroma, typically gaining entry to the circulation system through capillaries and thin-walled venules (eg, lymphatic channels). While the vast majority of circulating cells die, the detachment and embolization of single tumor cells or multicell aggregates occurs, and the surviving cells arrest in the capillary cells of distant organs, where they adhere to either capillary endothelial cells or to exposed endothelial membranes. This is followed by the extravasation of tumor cells into organ parenchyma, where tumor cell receptors respond to paracine growth factors and proliferate. For metastases to progress, the tumor cells must continue to evade host defenses and angiogenesis must again take place.
8. Cancer Biology: Angiogenesis In order to exceed a mass of 1 to 2 cm, angiogenesis—or the establishment of a capillary network from the surrounding host tissue—is essential. Angiogenesis is achieved through a series of processes originating from microvascular endothelial cells, and which are mediated by multiple molecules released by both tumor and host cells. The balance between stimulating and inhibiting factors determines the extent of angiogenesis. Benign neoplasms tend to have a limited vascular network, and therefore, tend to grow slowly. A greater degree of vascularization facilitates metastasis. Several studies indicate that the level of neovascularization may have implications for prognosis and survival.
9. Cancer Biology: Cell Cycle An understanding of the normal cell cycle has implications for cancer treatment. In the G 1 phase the cell prepares for DNA synthesis, which will occur in the S phase. There is a point in this phase, known as the R point, when the cell is committed to continue on into the S phase. During the S phase, a cell replicates its DNA. During the G 2 phase, DNA synthesis has been completed. During this transition phase prior to mitosis, protein, RNA, and other macromolecules are synthesized, albeit often in smaller amounts than the earlier G 1 phase. Finally, in the M phase, chromosomes condense and segregate, then, following separation, recondense.
10. Cancer Biology: The Doubling Process Tumors grow exponentially, since after the malignant transformation of a single cell, each cell divides to produce two daughter cells. Cells in rapidly-growing tumors may double every one to four weeks, whereas slowly-growing tumors may double every six months. Tumor cells that double every three months will have undergone the doubling process 20 times in 5 years; this tumor would then contain approximately 1 million cells and only have grown to the size of a pin head. After 30 doublings, the tumor will be detectable as a lump and by 41 to 43 doublings the tumor will overwhelm the patient, resulting in death.
11. Cancer Biology: Tumor Growth and Detection The growth of tumors follows a sigmoidal curve, from a single transformed cell through billions of cancerous cells. With current limitations of clinical detection, tumors may remain undetectable until they reach the diagnostic threshold of approximately 1 cm in diameter and contain 1 billion cells. If the steep rate of tumor growth continues, progression from detection of cancer to host death will occur within the period of time required for the tumor mass to reach 10 12 cells.
12. Cancer Biology: Dormancy of Tumor Cells The rate of growth of malignant cancer cells can be highly variable, ranging from extremely rapid doubling to essentially no growth or dormancy. Dormant cells can remain viable for many years after successful treatment of the primary tumor and emergence from dormancy can lead to disease recurrence. The precise mechanisms of dormancy remain unknown, but at least two possible explanations have been proposed. Metastatic tumor cells may enter a state of dormancy by arresting in the G 0 phase of the cell cycle in an isolated site within the body. Alternately, micrometastatic cells may continue to cycle, but the rate of cell division may be counterbalanced by a similar rate of cell death, perhaps due to a failure of the tumor to vascularize.
Tumorigenesis Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. Initial genetic change (eg, loss of function of pRb or overexpression of c-myc) Decrease in apoptosic cell death Subsequent genetic change Normal cell Increase in cell proliferation and apoptosic cell death Secondary genetic change (eg, dysfunction of p53 or overexpression of bcl-2) Further alterations in phenotype (eg, invasiveness and metastasis)
Emergence of tumor cell heterogeneity Primary Neoplasm Metastases TRANSFORMATION TUMOR EVOLUTION METASTASIS TUMOR EVOLUTION AND PROGRESSION AND PROGRESSION
Host influences on metastatic disease Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.
CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Neovascularization Oncogene expression is rare Intermittent or coordinated growth factor secretion Presence of tumor suppressor genes Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells Normal cell Few mitoses Cancer cells vs normal cells
Precancerous conditions Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279.
Growth factor Growth factor receptor Paracrine (adjacent cells) Growth factor and receptor synthesis Post receptor signal transduction pathways Gene activation Oncogenes Autocrine stimulation The role of oncogenes
Pathogenesis TRANSFORMATION ANGIOGENESIS MOTILITY & INVASION Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION EXTRAVASATION INTO ORGAN PARENCHYMA RESPONSE TO MICROENVIRONMENT TUMOR CELL PROLIFERATION & ANGIOGENESIS METASTASES METASTASIS OF METASTASES TRANSPORT Multicell aggregates (Lymphocyte, platelets)