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bacterial colonic flora, ingested foods, or endogenous metabolites such as fecapentaenes, 3-ketosteroids, and benzo[]pyrenes are mutagenic. Levels of these substances can be reduced by low-fat and high-fiber diets, and several epidemiologic studies confirm that such diets reduce the risk of colon cancer.

Furthermore, because the risk of sporadic colon cancer in older individuals is mildly elevated in the presence of a positive family history, there may be other inherited genetic abnormalities that

interact with environmental factors to cause colon cancer. The sequence of genetic changes may not need to be exact to lead to the development of an invasive cancer, although there is mounting evidence that some genetic lesions tend to develop early, whereas others may develop late in the course of the natural disease. All phenotypic changes cannot be explained by a known genetic abnormality, nor do all identified genetic alterations have a known phenotypic result. However, the stepwise nature of genotypic and phenotypic abnormalities is well established.

The earliest molecular defect in the pathogenesis of colon cancer is the acquisition of somatic mutations in the APC gene in the normal colonic mucosa. This defect causes abnormal regulation of -catenin, which leads to abnormal cell proliferation and the initial steps in tumor formation.

Subsequent defects in the TGF- signaling pathway inactivate this important growth inhibitory pathway and lead to further tumor mucosal proliferation and the development of small adenomas.

Mutational activation of the K-ras gene leads to constitutive activation of an important proliferative signaling pathway, is common at these stages, and further increases the proliferative potential of the adenomatous tumor cells. Deletion or loss of expression of the DCC gene is common in the

progression to invasive colon cancers. The DCC protein is a transmembrane protein of the

immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth and or apoptosis. Mutational inactivation of p53 is also a commonly observed step in the development of invasive colon cancer, seen in late adenomas and early invasive cancers, and leads to loss of an important cell cycle checkpoint and inability to activate the p53-dependent apoptotic pathways. Identification of genetic abnormalities in the progression of colon cancer to metastatic disease is currently under investigation.

Breast Carcinoma

The female breast is a specialized gland that undergoes repeated cycles of growth factor and hormone-induced changes that define the different stages of breast development (fetal, pubertal, menstrual, pregnancy-associated, and lactational growth together with postlactational involution).

Deregulation in this complex biology leads to a diverse group of breast diseases inherently connected with growth factor or hormonal signaling. Factors associated with an increased risk of breast cancer development may provide clues to early driving forces. Prolonged usage of high doses of exogenous estrogen is a risk factor that implicates the estrogen signaling pathway.

In contrast, reduced exposure to estrogen protects against the development of breast cancer. This has been demonstrated in ovariectomized animal models of breast carcinogenesis and is confirmed by clinical studies demonstrating that women who have undergone oophorectomy at a young age have a significant reduction in their lifetime risk of developing breast cancer. The clinical success of antiestrogen therapies provides proof of principle of the essential role of estrogen signaling in the pathogenesis of breast cancer. Agents that inhibit the production of estrogen or the ability of estrogen to activate the ER are highly effective in the treatment of patients with early or advanced breast cancer, are active in halting disease progression in patients with preinvasive breast cancers,

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and are also active in the primary prevention of breast cancer in women at risk. However, although the central role of estrogen signaling in the pathogenesis of breast cancer is now well established, the evidence to date does not etiologically implicate genetic abnormalities of the ER or its

downstream targets in the development of breast cancer.

It appears that ER signaling is a physiological pathway existing in breast epithelial cells whose

continued signaling activity is favorable to, or perhaps even necessary for, the oncogenic process. Yet the estrogen signaling pathway is intact in only one half of patients diagnosed with breast cancer; the remaining half appear to have no expression of the ER or activity of the estrogen signaling pathway.

This has led some investigators to believe that ER-negative breast cancer is a different disease with an alternative pathophysiology. Most likely, there are common early molecular steps in the

development of ER-positive and ER-negative breast cancers; however, at an early or intermediate step, these pathways diverge, leading to the development of breast cancers with distinctly different phenotypes.

68. Mesenchymal, neuroendocrine & germ cell neoplasia. Carcinoid tumors, testicular cancer & sarcomas

Mesenchymal, Neuroendocrine, & Germ Cell Neoplasia

Mesenchymal, neuroendocrine, and germ cell neoplasms account for a large proportion of the tumors of childhood and young adulthood, ostensibly because these cells are actively dividing and more subject to mutational events. Owing to the extensive migration and convolution of embryonic cell layers during early development, these tumor types may not evolve in specific anatomic sites.

Neuroendocrine tumors are derived from cells that migrate throughout the body and have developed specific enzymatic capabilities and accumulation of cytoplasmic proteins that serve a secretory function. As such, they are frequently identified by certain enzymatic markers, in particular, nonspecific esterase. Not all neuroendocrine tumors can be traced to the neural crest. Indeed tumors of this classification may not have a common embryonic ancestry. Neuroendocrine tumors can secrete biologically active peptides and produce specific clinical syndromes because of their secretory activities. Germ cell tumors can arise within the testes or in extragonadal sites through which germ cells migrate during development. Mesenchymal cells, by virtue of their function, are distributed throughout the body, and mesenchymal tumors can arise at any anatomic site.

Carcinoid Tumors

Carcinoid tumors are one type of neuroendocrine tumor. They arise from neural crest tissue and, more specifically, from enterochromaffin cells, whose final resting place after embryonic migration is along the submucosal layer of the intestines and pulmonary bronchi. Reflecting this embryonic origin, carcinoid cells express the necessary enzymes to produce bioactive amines such as 5-hydroxytryptamine and other vasoactive serotonin metabolites as well as a variety of small peptide hormones. Cytoplasmic granules typical of neuroendocrine cells are also commonly seen. The anatomic distribution of primary carcinoid tumors is consistent with embryonic development patterns. Carcinoid tumors and other mesenchymal neoplasms have similar patterns of tissue invasion followed by local and distant spread to regional lymph nodes and distant organs. The characteristics of increased mitotic count (an indicator of rapid proliferation), nuclear pleomorphism, lymphatic and vascular invasion, and an undifferentiated growth pattern are associated with a higher rate of metastases.A frequent site of carcinoid metastasis is the liver.

Testicular Germ Cell Cancer

Testicular cancer arises chiefly from germ cells within the testes. Germ cells are the population of cells that give rise to spermatozoa through meiotic division and can, therefore, theoretically retain

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the ability to differentiate into any cell type. Some testicular neoplasms arise from remnant tissue outside the testes owing to the midline migration of germ cells that occurs during early

embryogenesis. This is followed by the formation of the urogenital ridge and eventually by the aggregation of germ cells in the ovary or testes. By this pattern of migration, extragonadal testicular germ cell neoplasms are found in the midline axis of the lower cranium, mediastinum, or

retroperitoneum. The pluripotent ability of the germ cell is most evident in benign germ cell tumors such as mature teratomas. These tumors often contain differentiated elements from all three germ cell layers, including teeth and hair in lesions termed dermoid cysts. Malignant teratomas can also exist as a spectrum bridging other germ cell layer-derived neoplasms such as sarcomas and epithelium-derived carcinomas. Malignant testicular cancers may coexist with benign mature teratomas, and the benign component sometimes becomes apparent only after the malignancy has been eradicated with chemotherapy.

Proteins expressed during embryonic or trophoblastic development such as alpha-fetoprotein and human chorionic gonadotropin can be secreted and measured in the serum. Testicular carcinoma follows a lymphatic and hematogenous pattern of spread to regional retroperitoneal nodes and distant organs such as lung, liver, bone, and brain. The testicular cancers are sensitive to radiation and chemotherapy.

Sarcomas

The sarcomas consist of a family of mesenchymal neoplasms whose morphologic appearance and anatomic distribution mirror the early mesenchymal elements from which they derive. They arise in structures composed of the mesenchymal cell type or in locations where remnant cells eventually come to rest in the path of early tissue migration. Several of the less mature sarcomas that resemble more primitive cells are seen in children, because this compartment of cells is usually dividing more rapidly. These sarcomas include rhabdomyosarcoma and osteosarcoma, which are less common in adults.

The morphologic appearance of sarcomas does not involve perceptible architectural changes, because cell polarity and gland formation do not occur in normal mature mesenchymal cells such as muscle or cartilage. Nuclear pleomorphism and mitotic rate determine the grade of a tumor; a higher grade correlates with a higher propensity to invade local and distant structures and a poorer survival.

Sarcomas also have a tendency to retain the cell appearance and repertoire of expressed proteins of the cell of origin. There is less of a propensity for direct tissue invasion by sarcomas than by epithelial malignancies. However, tissue destruction can result when a sarcoma compresses but does not invade adjacent tissue, leading to the formation of a pseudocapsule. Sarcomas exhibit metastatic dissemination to regional lymph nodes and distant organs, especially the lungs. High-grade histologic features and anatomic location are factors influencing the likelihood and timing of metastases.

Mutations in the p53 tumor suppressor gene are the most commonly detected lesion. The NF1 tumor suppressor gene was originally identified through a germline mutation of this gene in patients with type 1 neurofibromatosis. This inherited syndrome is characterized by café-au-lait hyperpigmented skin spots and multiple benign neurofibromas (benign tumors of Schwann cells) under the skin and throughout the body. These can degenerate into malignant neurofibrosarcomas (malignant schwannoma). NF1 mutations have since been detected in sporadic sarcomas of different types.

Defective or absent activity of the NF1 protein is known to cause enhanced activation of the G protein-signaling pathways.

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