Acromegaly and Cancer

Acromegaly and Cancer: Not a Problem?

Acromegaly is usually caused by a GH-secreting pituitary adenoma. Somatic growth and metabolic dysfunction occur subsequent to unrestrained GH secretion and elevated insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 levels (1) (Fig 1). Classic clinical features of acromegaly include acral overgrowth, sweating, headaches, menstrual disturbances, and glucose intolerance (Table 1) (2). Well-documented clinical risks of long-term tissue exposure to uncontrolled GH hypersecretion include cardiac disease and hypertension, diabetes, respiratory disorders, joint disease, and neuropathy (Table 2) (3). The degree of risk for malignancy in these patients is unresolved; and acromegaly, representing an experiment of nature, could answer the question of whether or not elevated GH and IGF levels provide a permissive growth advantage for neoplasms, resulting in more aggressivemalignant disease and/or increased cancer-associated mortality (4).

Analysis of the determinants for mortality outcome in acromegaly indicates that approximately 60% of patients succumb to cardiovascular disease; 25% of patients, the cause of death is attributed to malignancy (Table 2). Nevertheless, absolute circulating GH values seem to constitute the most significant single determinant of survival, regardless of the cause of death (5-14). Several recent compelling studies support the critical role of GH, suggesting that GH control is associated with reversal of adverse mortality rates, regardless of the nature of associated co-morbidity (13). Thus, suppression of GH to less than 1 ng/mL, during an oral glucose tolerance test, and normalization of IGF-I levels portend a favorable mortality outcome (15).

Pathogenesis of somatic dysfunction in acromegaly

Peripheral tissue somatic growth and metabolic dysfunction are caused by direct effects of GH on peripheral receptors, impact of hepatic-derived circulating and paracrine IGF-I, and also the impact of elevated circulating IGFPB-3 levels. Elevated IGF-I bio-activity and activation of the IGF-I receptor are associated with cell proliferation and growth advantage, whereas IGFBP3 bio-activity promotes an apoptotic advantage (16-19). Thus, excess GH, by inducing both IGFBP3 and IGF-I levels, promotes dysregulated cell growth balance characterized by dynamic signals for cell apoptosis vs. cell growth advantage (Fig 2).

Because IGFBP-3 levels are high in acromegaly (20) (Fig 3) and correlate with IGF-I levels, an imbalance of circulating IGFBP-3 level vs. IGF-I action is manifested by the broad spectrum of clinical somatic features of the disease and is reflective of a broad range of respective circulating values for these two factors in patients with acromegaly. This is especially noteworthy because, in vitro , IGFBP-3 inhibits IGF-I-induced prostate cancer cell growth (21) (Fig 4), and breast cancer cells are diverted into an apoptotic phase by IGFPB-3 (22). In acromegaly, the activated IGF-I receptor accounts for increased kidney, heart, or acral bony tissue functional cell mass. These patients, therefore, potentially harbor a tumor growth advantage mediated by IGF-I activated cell renewal and increased functional mass; whereas concomitantly, elevated IGFBP-3 accounts for an enhanced cell removal process and apoptosis (23). Thus, pathologically elevated GH results in peripheral tissue exposure to both excessive growth-promoting and growth-arresting influences.

The role of the GH-IGF-I axis in tumorigenesis has been extensively studied. In vitro evidence supporting the role of these growth factors in development of neoplasia includes reports that GH and IGF-I readily transform lymphocytes, and also induced cell proliferation. IGF-I receptor mass is increased in neoplastic tissues, and the activated IGF-I receptor also mediates cell transformation (16, 17, 19-26). Several growth factors and inactivated tumor-suppressing genes also stimulate IGF-I receptor synthesis (18). However, there are no reports of enhanced spontaneous tumor formation in IGF-I-expressing transgenic mice (27). Targeted expression of IGF-I by a human keratin promoter was shown to result in epidermal hyperplasia and hyperkeratosis, with enhanced sensitivity to tumor induction by administered TPA (28). These latter observations suggest a permissive, rather than an initiating, role for IGF-I in tumorigensis. In classic earlier papers by Moon and colleagues (29), impure extracted GH was injected into rats at very high doses (up to 3 mg/day) for up to 16 months, and these animals developed primarily lymphoid hyperplasia and lung lymphosarcomas. In vivo , GH induces neoplasm formation and also c-myc expression in experimental models, and mice overexpressing GH transgenes develop tumors over the long term (30-31). Several decades of earlier experience with hypophysectomy showed the procedure to be protective or palliative for patients with neoplasia (32). Somatostatin administration lowers IGF-I levels and also retards transplanted tumor growth in some animal models. Thus, several lines of in vitro and in vivoevidence indicate a role for the GH-IGF-I axis in mediating both physiologic and pathologic cell growth and tissue hypertrophy (19). The impact of this cumulative experimental evidence on risk for tumorigenesis in patients with acromegaly remains unclear.

For patients with acromegaly, it seems that controlling GH levels, hypertension, and heart disease are important for improving ultimate mortality. Fifteen percent of deaths in acromegaly are attributable to malignancies, which is lower than would be expected from the general population, and confirmed by Orme (Table 2). Uncontrolled acromegaly may provide a growth advantage to concurrently occurring neoplasms in these patients; and based upon experimental information, cancer in a patient with acromegaly and uncontrolled GH levels will likely be more aggressive, with potentially increased cancer-associated morbidity and mortality.


 References:

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The Journal of Clinical Endocrinology & Metabolism
Shlomo Melmed   2000, Vol. 86, No.7, pp. 2929