Guanylyl Cyclase C in Colorectal Cancer: Susceptibility Gene and Potential Therapeutic Target

Abstract

SUMMARY Colorectal cancer is one of the leading causes of tumor-related morbidity and mortality worldwide. While mechanisms underlying this disease have been elucidated over the past two decades, these molecular insights have failed to translate into efficacious therapy. The oncogenomic view of cancer suggests that terminal transformation reflects the sequential corruption of signal transduction circuits regulating key homeostatic mechanisms, whose multiplicity underlies the therapeutic resistance of most tumors to interventions targeting individual pathways. Conversely, the paucity of mechanistic insights into proximal pathophysiological processes that initiate and amplify oncogenic circuits preceding accumulation of mutations and transformation impedes development of effective prevention and therapy. In that context, guanylyl cyclase C (GCC), the intestinal receptor for the paracrine hormones guanylin and uroguanylin, whose early loss characterizes colorectal transformation, has emerged as a component of lineage-specific homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis. Dysregulation of GCC signaling, reflecting hormone loss, promotes tumorigenesis through reprogramming of replicative and bioenergetic circuits and genomic instability. Compensatory up-regulation of GCC in response to hormone loss provides a unique translational opportunity for prevention and treatment of colorectal tumors by hormone replacement therapy.

Challenges in the Management of Stage II Colon Cancer

“…GCC is an interstitial tumor suppressor which is selectively expressed in normal intestinal epithelium and overexpressed in malignant gastrointestinal cells [93]. Dysregulation of GCC promotes tumorigenesis.…”

The Paracrine Hormone for the GUCY2C Tumor Suppressor, Guanylin, Is Universally Lost in Colorectal Cancer

“…They suggest that silencing of this tumor suppressor during transformation is functional reflecting loss of guanylin, rather than oncogenomic reflecting tumor suppressor mutations (5, 38). Studies here confirm this hypothesis in a large cohort of patients with colorectal cancer.…”

“…In that context, it is tempting to speculate that the substantial reduction (>95%; see Table 2) in guanylin expression in normal epithelia in people >50 yo revealed here might contribute mechanistically to the established epidemiological vulnerability of this population to colorectal cancer (1, 39). These mechanistic considerations suggest that colorectal cancer might initiate as a disease of paracrine hormone insufficiency (5, 38). Like other diseases of endocrine insufficiency reflecting hormone loss, but preservation of receptor expression, silencing GUYC2C might be prevented by therapeutic replacement of GUCY2C ligands.…”

Molecular staging individualizing cancer management

“…In close agreement, silencing GUCY2C signaling increases tumors in mouse models of genetic and carcinogen-based tumorigenesis, reflecting dysregulation of proliferation and chromosomal instability [66]. Indeed, GUCY2C is a tumor suppressor organizing the crypt-surface axis whose dysregulation reflecting loss of paracrine hormone expression contributes to intestinal neoplasia [64-67,71]. …”