cAMP/PKA signaling defects in tumors: genetics and tissue-specific pluripotential cell-derived lesions in human and mouse

Abstract

In the last few years, bench and clinical studies led to significant new insight into how cyclic adenosine monophosphate (cAMP) signaling, the molecular pathway that had been identified in the early 2000s as the one involved in most benign cortisol-producing adrenal hyperplasias, affects adrenocortical growth and development, as well as tumor formation. A major discovery was the identification of tissue-specific pluripotential cells (TSPCs) as the culprit behind tumor formation not only in the adrenal, but also in bone. Discoveries in animal studies complemented a number of clinical observations in patients. Gene identification continued in parallel with mouse and other studies on the cAMP signaling and other pathways.

Figure 1

Three iMADs from 3 different patients; none was inherited, there were no PRKAR1A, PDE11A, PDE8B, or GNAS defects, and they showed varying degrees of hyperplasia, pigmentation and nodularity.

Figure 2

PBAD due to a GNAS mutation (Carney et al., 2011): the arrow points to hyperplastic cortex. Histology, to the right, shows variegated appearance with alternating areas of hyperplasia interspersed with areas of cortical atrophy. PBAD appears to be forming from expansion of fetal islets that are supposed to involute as the adult cortex forms.

Figure 3

Osteoblast-like cells started filling the marrow in young animals (ovoid); they always expanded from the same location in the diametaphyseal region, immediately under the growth plate, from the proximal periosteum and nearby trabecular bone.

Figure 4

A. High expression of pre-osteoblastic transcription factor Ets1 in Prkar1a^+/−Prkaca^+/− bone tumors. PKA catalytic subunits increased Ets1 expression; Ets1 activates caspase 1 (casp1) and other components of the inflammasome. B. Increased casp1 expression in Prkar1a^+/−Prkaca^+/− bone tumors against those of the Prkar1a^+/− mice; IL1B was also highly expressed in Prkar1a^+/−Prkaca^+/− bone tumors, especially against bone tissue from the Prkaca^+/− mice. C. Increased PGE-2 levels in the cells from bone tumors from the Prkar1a^+/−Prkaca^+/− and the Prkar1a^+/− mice, against MC3T3 osteosarcoma cells. D. Effect of Ac-YVAD-CMK, a selective and irreversible casp1 inhibitor, on the proliferation of MC3T3 osteosarcoma cells and those from bone lesions from Prkar1a^+/−Prkaca^+/− and Prkar1a^+/− mice; the proliferation of Prkar1a^+/−Prkaca^+/− cells was significantly inhibited. PGE2 and cAMP levels also decreased (data not shown) in response to the casp1 inhibitor.

Figure 5

Pluripotential cell-derived endocrine (and other) tumors, as some cancers, may be formed (lower panel) by stem cells or tissue-specific pluripotential cells (TSPCs). These cell differentiate and mature during life (upper panel), in fetal and then adult tissues, respectively, leaving always a small population of cells (light green color) within the organs/glands that are there retaining regenerative/healing capacity; it is possible that only the elderly tissues (last collection of cells in upper panel) do not retain substantial number of TSPCs and that may also be organ-specific. However, at any time, these pluripotential cells may become the origin of a benign (blue) or malignant (red) neoplasm, shown by the multiple arrows, as a result of genetic or epigenetic alterations. In other words, TSPC-derived lesions may originate in early life (lower panel) without these cells ever differentiating (lower panel) or could form later in life from the residual pluripotential cells in mature tissues (upper panel).