Ectopic Production Of Hormones By Tumor Cells

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There are many examples of tumors producing hormones that are unrelated to the tissue of origin. This only underscores the dedifferentiated state of the cancer cell. Apparently there is no clear understanding of the reason for the production of a specific unexpected hormone by a given tumor cell, except that rearrangements of genes may occur and the rearranged gene may insert next to a highly expressing sequence and be overproduced. Thus, the term "ectopic" is used, which refers to the generation of a hormone away from the normal site of its production.

Various tumors have been shown to secrete ACTH and to cause hypercortisolism, even when the tumor is undetectably small for many years. The secretion of this hormone ectopically occurs mainly with bronchial carcinoid tumors and to a smaller degree with pheo-chromocytomas, thymic carcinoids, and islet cell tumors. The carcinoid tumors can be very difficult to locate. This condition can lead to Cushing's syndrome, characterized by overproduction of Cortisol from the adrenal gland as a result of the uncontrolled levels of ACTH or its stimulating hormone, CRH, derived directly from ectopic production of the hormone. These tumors can also secrete proopiomelanocortin-related peptides.

The ectopic production of parathyroid hormone and concomitant hypercalcemia are somewhat rare. However, they have been shown to occur in a case of small cell carcinoma of the lung and in a case of ovarian carcinoma. Computed tomography of the abdomen revealed a right ovarian mass 5-8 cm in size. When the cancer was removed, the level of PTH declined. Molecular analysis revealed rearrangement of the upstream region of the PTH gene, as shown in Figure 20-6.

A case was reported of acromegaly from ectopic growth hormone-releasing hormone (GHRH) secreted to an extent 1000 times greater than normal by a bron-

Rearranged and amplified PTH-gene region - ses up

FIGURE 20-6 PTH gene region in the ovarian carcinoma. (A) shows the results of Southern blot analysis of the PTH gene region in the ovarian carcinoma. DNA (10 fig) from the peripheral blood leukocyte control (C) and from the ovarian tumor (T) was digested with the indicated restriction endonucleases and analyzed. The bands normally expected are indicated by dashes, while the abnormal, rearranged bands are indicated by arrows. Band sizes are in kb corresponding to the linear map in (B). (B) shows restriction maps of the normal PTH region (top) and the rearranged and amplified PTH gene region in the ovarian tumor (bottom). PTH exons I, II, and III are represented by open bars, introns normally present and flanking regions are represented by solid bars, and the cross-hatched bar represents the DNA placed upstream of PTH by the rearrangement. Shaded rectangles represent the fragments of normal PTH used as probes. At the bottom, —562 bp marks the upstream HmdIII site aligned above it in (A), which is the 3' border of the 150-bp Bglll-HmdIII segment that contains the precise breakpoint. Reproduced with permission from Nussbaum, S. R., Gaz, R. D., and Arnold, A. (1990). New Eng. J. Med. 19, 1324-1328.

chial carcinoid tumor. In this case, plasma growth hormone levels were increased. There was metastatic disease demonstrated by the production of GHRH and GH by tumor tissue in the lung, submaxillary gland, and breast. The condition was treated with chemotherapy (nitrosourea, CCNU, and 5-fluorouracil in repeated cycles) and the tumors regressed. This is a rare syndrome and also unusual in its positive response to chemotherapy since carcinoid tumors are not known for this susceptibility.

These are but a few examples out of a great many in which hormones can be produced by tumors, and these ectopic hormones are able to abrogate the normal hormonal homeostatic mechanism. In general, the descriptions given may be relatively rare, and it seems possible that in many cases of ectopic production of hormones there is aberrant production of tissue-specific transcription factors that, in the normal tissue counterpart, would not be produced.

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