Chapter 7: Neoplasia
The term neoplasm historically hasn’t been well defined. Currently, Robbins and Cotran define it as: “…a disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny.” Causative mutation in neoplastic cells impart advantages in autonomous proliferation. A tumor are made up of a neoplastic cells or tumor parenchyma, which can stimulate abundant formation of collagen in its reactive stroma or network of connective tissue, blood vessels, and cells with “adaptive and innate immune systems.” These tumors are called desmoplasia such as stony, hard scirrhous breast tumors. Other tumors may only have scant connective rendering them soft and fleshy.
In general, benign tumors—localized, non-metastatic, and amenable to surgical excision—are designated with the type of tissue from which it originated and the suffix -oma. Tumor of epithelia tissues are excluded from this rule and are instead classified based on cell origin or micro/macroscopic characteristics. Adenomas (glandular tumors), papillomas (“fingerlike or warty” projections from epithelial surfaces), cystadenomas (cystic masses), polyp (projections above a mucosal surface), or any combination there of may serve as and example.
Tumors that can invade and destroy adjacent structures, and spread to distant sites to cause death are termed malignant and are collectively referred to as cancers. If a tumor is malignant, it is usually named by its structural characteristics. Tumors consisting of solid mesenchymal tissues are termed based on the tissue type and the suffix -sarcoma (or a slight variation) (e.g. fibrosarcoma, rhabdomyosarcoma, leimyosarcoma). While those of blood-forming cells are called leukemias and those of lymphocytes are lymphomas. Tumors involving any of the three germ layers (i.e. ectoderm, mesoderm, endoderm) are termed carcinomas and can be further classified based on cell type (e.g. adenocarcinoma). Still tumors that have an unknown origin are merely called undifferentiated malignant tumors.
In some cases a cells of a single clone and diverge in differentiation and hence consist of more than one cell type. A tumor arising from a salivary gland that contains both epithelial tissues and mixtures of bone is designated as a pleomorphic adenoma, for example. Tumors that arise from totipotential germ cells stem cells—usually in the ovaries or testis—that have recognizable (im)mature cells are termed teratoma.
Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells morphologically and functionally. Benign tumors are well differentiated and may not even appear to be to a neoplastic growth under the microscope lacking defining features such as mitotic bodies. Malignant neoplasms may be well-differentiated that are identical to normal paraenchyma or completely undifferentiated (anaplastic “to form backward”) cells that make identification of the origin of the tumor difficult or impossible. Anaplasia and lack of differentiation—considered one of the hallmarks of cancer—can take several different forms:
Pleomorphism—Variation in size and shape of the cells and its components. May have a large nucleus, multiple nuclei, hyperchromatic nuclei. Not to be confused with inflammatory or immune response.
Abnormal nuclear morphology—The nuclear-to-cytoplasm ratio may approach 1:1 rather than 1:4 or 1:6. Nuclei can be also have irregular shape and be hyperchromatic.
Loss of polarity—Sheets and large masses of cells can grow in anarchic, disorganized fashion.
Other changes—Evidence of ischemic necrosis.
If a tumor cell is well differentiated, it may be identified by increased activity; adenomas may secrete more hormones, carcinomas may secrete more keratin, hepatocellular carcinomas may elaborate bile.
Metaplasia is defined as a replacement of cell types and is typically found in association with tissue damage, repair, or regeneration so that a cell is better suited for a change in the environment. (Gastic or intestinal epithelial metaplasia for the squamous epithelium of the esophagus be cause of gastroesohageal relux is a classic example).
Dysplasia can refer to number of changes that include: loss of uniformity or architectural origin; hyperchormatic nuclei; or high nuclear-to-cytoplasmic ratio. Dysplastic changes that involve the full thickness of the epithelium but do not penetrate the basement membrane considered preinvasive cancer or carcinoma in situ and when it crosses the basement membrane it is called invasive.
Benign tumors are typically surrounded by a capsule or a well defined rim of compressed fibrous connective tissue mostly composed of extracellular matrix secreted by stromal cells that are activated by hypoxic stress resulting from the growing mass. This capsule makes tumors discrete, movable, and easily excisable. Hemangiomas, however, are an unencapsulated tangled mass of blood vessels that are integral to the site of origin often making rescission impossible. In contrast, malignant tumors have no such discriminating plane though some slower growing invasive tumors can develop a pseudoencapsulation. Invasiveness is one the most reliable distinguishing features of cancer.
Metastasis or the spread of neoplasms to physically discontinuous sites is an unequivocal marks a tumor as malignant. By definition malignant tumors can metastasize though some rarely do (e.g. gliomas and basal cell carcinomas); their invasive behavior implies their ability to metastasize.
Metastasis is correlated with lack of differentiation, aggressive invasion, rapid growth rates, and size though many factors affect the probability of metastasis. Once solid tumors metastasize the probability of a cure is significantly reduced. Liquid tumors such as leukemias or lymphomas are malignant, per se.
Seeding can occur when a malignant neoplasm invades and area where there is no physical barrier: peritoneal, pleural, pericardial, subarachnoid cavities or joint spaces—where they may remain confined. Seeding is characteristic of mucus-secreting ovarian and appendiceal cancers, which spread and coat the peritoneal cavity with a gelatinous neoplastic called pseudomyxoma peritonei.
Carcinomas typically spread though the lymph system first though sarcomas can use also use this system. Node involvement of a malignant neoplasm follows the natural routes of lymphatic drainage; breast carcinomas originating in the upper, outer quadrants drain first to the axillary nodes, inner quadrants drain to nodes along the internal mammary arteries before involving the infraclavicular and supraclavicular nodes. Lung carcinomas drain first to perihilar tracheohronchial and medisatinal nodes. Local nodes can be skipped due to venous-lymphatic anastomoses or obliteration of the lymphatic channels by inflammation or radiation.
Sentinel nodes—the first lymph node in a regional lymphatic basin that receives lymph flow from the primary tumor—are useful in staging or identifying the presence of metastatic lesions though biopsies. They can be mapped though radioactive labeling and examination of sections during surgery can determine appropriate therapy. Other regional nodes my become hyperplastic because they are arresting metastasis and mounting an immune response to the tumor. Hence, enlarged regional nodes may not necessarily be a metastatic lesion.
Sarcomas typically use veins for hematogenous spread as arterial walls are typically too thick to be easily penetrated though arterial spread does occur when tumor cells pass through pulmonary capillary beds, arteriovenous shunts, or when pulmonary metastase give rise to tumor emboli. Venous invasions often take hold in the site of the first capillary bed typically in the liver and lungs due to portal and caval blood flows, respectively. Cancers originating from sites near the vertebra travel trough the paravertebral plexus typically to the thyroid or prostate. Certain cancers have preference for particular veins: renal cell and hepatocellular carcinomas for the renal vein and protal/hepatic radicles, respectively. Still others do have preferences not readily explained by venous drainage: beast carcinomas ans bode, bronchogenic carcinomas and adrenal glands/brain, neuroblastomas and liver/bones. Skeletal muscle and spleen are rarely the sites of metastases.
There are four central themes at the heart of the development of cancers
Nonlethal genetic damage lies at the heart of carcinogenesis such as exogenous exposure to environmental agents and be inherited in the germline.
Tumors are formed by clonal expansion of precursor cells that incurred genetic damage, which can be identified by cytological techniques.
There a four classes of non-pathogenic genes that when mutated contribute to development of cancer: proto-oncogenes (growth promoting), tumor suppressor genes (growth suppressing), apoptosis-regulating genes, and DNA repair genes.
Carcinogenesis results from the accumulation of complementary mutations over time.
The phenotypes of malignant neoplasms are called the cancer hallmarks.
Mutations that contribute to the development of cancer hallmarks are referred to as driver mutations.
Loss-of-function mutation in genes that maintain genomic integrity appear to be a common early step. Mutations such as these that do not have an observable phenotype but contribute to malignancy are called passenger mutations.
Tumor progression is used to describe the phenomena of darwinian selection of increasingly more aggressive and malignant sub-clones with each division. This phenomena no only explains the genetic diversity within a malignant mass but also the development of resistance to antineoplastic therapeutics.
Epigenetic modification such as DNA methylation and histone modification may also play an important role in development of malignancy, most obviously, silencing of tumor suppressor genes.
While there are a increasingly innumerable set of mutations that might be used to characterize an innumerable number of cancer types a more tractable model for cancer is characterized by the 8 hallmarks or phenotypes of cancer.
Oncogenes are created by mutations in proto-oncogenes that ultimately encode onocoproteins, which resemble normal products but inactivate regulatory elements making activity independent of external signals; this can occur at one of several step of the growth factor signaling pathway model.
Binding of growth factor to its respective receptor
Transient and limited activation of the growth factor, which can activate cytoplasmic signal transducing pathways
Transmission of the transduced signal to the nucleus via additional cytoplasmic effector proteins and second messengers or by a cascade of signal transduction
Induction and activation of nuclear regulatory factors that initiate DNA transcription
Expression of factors that promote entry and progression of the cell into the cell cycle and ultimately resulting in cell division
In parallel, changes in the expression of other genes that support cell survival and metabolic alterations that are needed for optimal growth
While there are many pathways that can be involved onocogenesis: G protein-coupled receptors, JAK/STAT, WNT, Notch, Hedgehog, TGF-β/SMAD, NF-κB—receptor tyrosine kinase pathways are the main focus of this chapter.
Proto-oncogenes participate in signaling pathways that drive growth proliferation such as: encoding growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle component—mutations typically cause constitutive activity.
Most soluble growth factors for proliferation are a paracrine single while cancers typically acquire autocrine signaling abilities. As examples glioblastomas express both platelet-derived growth factor (PDGF) and the PDGF receptor tyrosine kinase while sarcomas express TGF-α and its receptor EGFR. The growth factor genes are not usually altered in tumors with this kind of autocrine loop. Rather, signals transduced by other oncoproteins cause over expression of receptors and increased section of growth factors.
Point mutations, rearrangements, or amplification in receptor tyrosine kinase genes may cause constitutive activity of the receptors, which recruit signaling molecules such as RAS and PI3K. Some of clinical importance:
ERBB1—Encodes the epidermal growth factor receptor. Several point mutations are know to cause constitutive tyrosine kinase activity in a subset of lung cancers.
ERBB2—Encodes for HER2 (a member of the receptor tyrosine kinase family). Amplification of ERBB2 cause HER2 over expression and constitutive tyrosine kinase activity.
Gene rearrangements—A deletion on chromosome 5 can cause fusion of AKL (codes for tyrosine kinase AKL) with part of EML4, which genes a chimeric EML4-AKL oncoprotein leading to constitutive tyrosine kinase activity: a known cause of a subset of lung adenocarcinomas.
Iummnotherapeutic drugs have been developed to inhibit these receptors stop tumor growth and inducing apoptosis and tumor regression. Nonetheless, many cancers develop resistance to these drugs by activating other receptor pathways.
Receptor tyrosine kinase activation stimulates RAS and subsequently the MAPK cascade or the PI3K/AKT pathway making RAS particularly prone to oncogenic gain-of-function mutations. Constitutive RAS activity appear to complete substitute for tyrosine kinase activity. In fact, lung andenocarcinomas fall into mutually exclusive subtypes of RAS or receptor tyrosine kinase activity.
There are three genes in the RAS family: HRAS, KRAS and FRAS—that are estimated to be implicated in 15-20% of all human tumors (some types as much as 90%). No therapeutic agent targeting RAS has yet been successful due to its vague structure and mode of signaling.
As a member of the small G-protein family, RAS has an intrinsic GTPase activity—its mechanism of inactivation—that is further accelerated by GTPase-activating proteins (GAPs). There are known point mutation in RAS that reduce its GTPase activity as well as mutations in GAP genes such as NF1 (which causes familial neurofibromatosis type 1).
BRAF is a member of the RAF family of genes and codes for a serine/tyrosine kinase at the top of the MAPK signaling cascade ultimately activating transcription factors, among other molecules. Mutations in BRAF has been detected in nearly all hairy cell leukemias, most melanomas, and benign nevi. Mutations at any other point in the cascade are uncommon in cancers. Melanomas due to mutation sin BRAF have been strikingly responsive to therapeutic inhibitors.
PI3K is recruited by activated rector tyrosine kinases to the plasma membrane, and like with BRAF, it activates serine/tyrosine kinase cascade including the key signaling node: AKT, which activates mTOR an activator or lipid synthesis, inactivates BAD a pro-apoptotic protein, and pro-apoptotic transcription factors, FOXO, are negatively regulated by AKT phosphorylation. Mutations in genes that code for catalytic subunits of PI3K and PTEN, which codes for the antagonist of PI3K, are frequently found in breast and endometrial carcinomas, respectively.
There are many mutation that cause oncogenic activity of tyrosine kinase enzymes that are not receptors. As an example, a translocation of the ABL gene from chromosome 9 to the BCR locus of chromosome 22 is often the cause of tyrosine kinase activity leading to chronic myelogenous luekemia (CML). Drugs that treat CML have been very successful at therapeutic agents for all but the CML cancer stem cells. They inhibit the BCR-ABL onocoprotein of all but the cancer stem cells making treatment indefinite.
Mutations in genes coding for the nonreceptor tyrosine kinase enzyme JAK2, a protein that regulates the hematopoietic JAK/STAT pathway, is often found in myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, and primary myelofibrosis.
Mutations in mitogenic signaling pathways ultimately affect transcription factors for growth promoting or tumor suppressing genes. Therefore implying that mutations in transcription factors such as MYC, MYB, JUN, FOS and REL are also proto-oncogenes.
MYC is one of the transcription factors that is induced by the RAS/MAPK pathway and virtually all pathways that regulate growth impinge on MYC. There are small nucleotide polymorphisms (SNPs) that are linked to prostate and ovarian carcinomas likely because they are enhancers near MYC. While it is not completely understood MYC has been shown to:
Activate expression of genes involved in cell growth
Expression of D cyclin
Expression of rRNA genes
Metabolic reprogramming
May be the “master transcriptional regulator” of cell growth
Expression of telomerase
Aids in inducing pluripotency
Oncogenic mutations can take the form of direct alteration to MYC as well as translocation of MYC to other chromosomes, or amplifications.