Mechanisms Involved in Ectopic Hormone Production by Nonendocrine Neoplasms

1 Jun

In most of the examples given in Table 18.4, one might suggest that such a change in gene ex- pression is the result of defect(s) at the gene, transcription, or posttranscriptional level. Many of the mechanisms discussed in Chapter 15 would thus be applicable. However, another potential mechanism  is that related to posttranslational  processing  of polypeptides  such as depicted in Figure 18.5 with reference to the production of pancreatic hormones. Such appears to be the case for the production of ACTH, where a 31-kDa peptide is the initial translation product, then lead- ing to a variety of different products including ACTH, lipotropin, and β-endorphin,  as well as melanocyte-stimulating  hormone (MSH). A diagram of the posttranslational  processing of the precursor peptide proopiomelanocortin (POMC) is seen in Figure 18.9. It will be noted from this that ACTH is only one of many peptides produced by this posttranslational  processing mecha- nism. Wajchenberg and associates (1994) have presented evidence that probably all tissues syn- thesize at least small amounts of POMC-derived  peptides, but only in neoplasms  where it is produced in substantial amounts does one see significant clinical findings. Thus, one might ar- gue that the “ectopic” production  of ACTH by small-cell lung cancers and a variety of other tissues is not truly ectopic, since such tissues appear to have the capability of producing the pre- cursor. In other neoplasms,  however,  there is evidence  for differential  splicing of the POMC transcript, giving rise to different mRNA species, some of which may be associated  with the ectopic ACTH syndrome and others not (cf. Wajchenberg et al., 1994).

Overexpression of insulin-like growth factor-II (IGF-II) in mesenchymal and adrenal neo- plasms may be related to the loss of imprinting of the gene, as discussed in Chapter 15 (Gicquel et al., 1995). The high level of IGF-II may induce hypoglycemia by inhibiting the output of glu- cose from the liver (cf. Fradkin et al., 1989). However, these mechanisms may not comprise the majority of alterations leading to the elaboration of hormone-like  substances by nonendocrine neoplasms. It is tempting to speculate that in a number of instances the aberrant hormone pro- duction may be the result of evolving karyotypic instability with its associated gene amplifica- tion and gene translocations.

Paraneoplastic Syndromes Unassociated with Increased Production of

Known Hormones

The term paraneoplastic syndrome has been used to denote clinical signs and symptoms that are not directly related to the neoplasm or its metastases (cf. Eckhardt, 1994). This rather broad clas- sification would then include almost any determinant of the host-tumor relationship, including cachexia, anorexia, hormones elaborated by endocrine neoplasms, as well as hormones secreted by neoplasms  developing  from nonendocrine  tissues and the production  of nonhormonal  ele- ments leading to host responses resulting in specific syndromes. The clinical effects resulting in these syndromes are thus not dependent on the bulk of the neoplastic tissue but on its function- ing within the organism (Eckhardt, 1994). In this broad definition, one could perhaps include almost all neoplasms,  since all produce some remote effect not dependent  on the bulk or the invasive or metastatic characteristics of the neoplasm itself. Thus, as others have done (cf. Agar- wala, 1996; Zimmermann and Greenberg, 1996; Macaulay and Smith, 1995), the term paraneo- plastic syndromes is here restricted to those resulting from hormones elaborated by neoplasms of nonendocrine tissues, nonhormonal components elaborated by neoplasms but directly or indi- rectly inducing specific signs and symptoms in the organism, and physical effects resulting from overproduction  of products of the neoplasm. Already discussed are paraneoplastic  syndromes resulting from hormone production by neoplasms of nonendocrine tissues (see above); consid- ered below are the effects of nonhormonal components elaborated by neoplasms on the host.

Figure 18.9 Posttranslational  processing of proopiomelanocortin (POMC) in normal pituitary and in neoplasms of the ante- rior pituitary  and in ectopic ACTH-secreting  neoplasms.  The hatched areas indicate peptides  that are more abundant  in the pituitary, while the cross-hatched areas indicate melanocyte-stimulating hormone (MSH) sequences, and the black areas repre- sent “abnormal” polypeptide fragments seen in the ectopic ACTH syndrome. (From Wajchenberg et al., 1995, with permission of the authors and publisher.)

Paraneoplastic Syndromes Associated with Production of Nonhormonal Factors by the Neoplasm

By the definition indicated above, one could include cancer cachexia as a paraneoplastic  syn- drome; but generally this has not been done, since it is such a complex, little understood phe- nomenon that occurs to one degree or another in organisms bearing any malignant neoplasm. Table 18.5 shows a listing of a number of clinical syndromes associated with neoplasms but for which there is no known hormonal cause. Acanthosis nigrans—a lesion of the skin that is usu- ally symmetrical,  elevated,  rough-surfaced,  and hyperpigmented—is  usually associated  with carcinomas  of the gastrointestinal  tract, especially  the stomach, but it may also be seen with malignancies of the breast, prostate, lung, breast, and ovary (cf. Poole and Fenske, 1993). There has been some suggestion that this lesion may be related to the production of melanocyte-stimu- lating hormone (see above), but other suggestions  implicate  some as yet unknown  epidermal growth substance (cf. Poole and Fenske, 1993). Mucocutaneous  pigmentation is seen with the inherited Peutz-Jeghers  syndrome. This syndrome is associated with benign tumorous malfor- mations of the gastrointestinal  tract known as hamartomas,  which are probably not neoplastic (cf. Utsunomiya et al., 1975). Other mucocutaneous manifestations of paraneoplastic effects of neoplasms  have also been described  but are not included in the table (cf. Poole and Fenske,

1993; Herzberg, 1998; Kurzrock and Cohen, 1995). Arthralgia and hypertrophic pulmonary os- teoarthropathy (forms of arthritis) have long been known to be associated with neoplasms affect- ing the lung and pleura (cf. Naschitz et al., 1995). Hypertrophic pulmonary osteoarthropathy  is basically an overgrowth of soft tissue in the distal phalanges (fingers and toes) leading to a phe- nomenon  known as “clubbing.”  One of the first hematological  paraneoplastic  disorders  de- scribed was that of Trousseau syndrome, the association of thrombosis with malignancy. Deep vein thrombosis of the lower extremities and pulmonary embolism result from a hypercoagula- ble state induced by the neoplasm,  most commonly  a mucin-producing  neoplasm of the gas- trointestinal tract or of the lung and pelvic organs (cf. Staszewski, 1997). Multiple myeloma, a neoplasm of antibody-producing  plasma cells, in most instances produces excessive amounts of circulating immunoglobulins, which can deposit in various organs leading to renal failure, where there is actual blockage of the renal tubular system, and to amyloidosis, a disease characterized by extracellular deposition of complex proteins causing dysfunction of the organ by the presence of large amounts of amyloid (cf. Barlogie et al., 1992; Dhodapkar et al., 1997; Tan and Pepys,

1994). However, the most common paraneoplastic syndromes associated with neoplastic elabo- ration of nonhormonal  substances  are those related to autoimmune  reactions to proteins pro- duced by the neoplasms themselves. Autoimmunity is discussed more extensively in Chapter 19, but it is basically the immune reaction of the host to products of its own genetic makeup, so- called self-antigens.

Table 18.5 Paraneoplastic Syndromes Resulting from Excessive Production of Nonhormonal Components by Neoplasms

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