Aging, cancer, and wound healing.

Aging processes can be described as recognizable series of molecular events within vital organ systems whose dysfunction gradually increase with time (reviewed by [1]). This dysfunction manifests itself as abnormal increases and decreases in gene expression and these events occur at a rate that exceeds the relative rate at which they can be corrected. The outcome of this progression is a steady decline in the capacity to successfully maintain an organism's peak physiology, which occurs approximately around the time of sexual maturation. The resulting changes increase the likelihood that an organism will eventually approach a state of increased vulnerability to disease and ultimately leads to death. Within the context of both wound healing and cancer, molecular mechanisms of aging-related changes affect an organism's ability to repair damaged cells and tissues through disregulation of some common molecular pathways. In the case of the former, wound healing is impaired as a result of an inability to adequately express genes which facilitate escape from cell stasis in order to commence and complete the healing process. In the latter case, the failure of a cell's repair mechanism to correct damage to DNA can lead to neoplastic transformation of a normal cell into one with unlimited growth potential. This review compares several of the molecular and cellular events associated with cancer and wound healing during aging.

A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells.

Angiogenesis is impaired in aging. Delayed neovascularization is due, in part, to slowed endothelial cell migration. Migration requires an optimal level of adhesion to matrix proteins, a process mediated by matrix-degrading metalloproteases (MMPs) such as MMP1. To determine whether impaired angiogenesis in aging is associated with altered synthesis and activity of MMP1, we examined the expression of collagenase and tissue inhibitor of metalloprotease 1 (TIMP1) by immunostain of angiogenic sponge implants from young and aged mice. To characterize the relevance of MMP activity during the movement of aged endothelial cells, the secretion of MMP1 and TIMP1 by late-passage human microvascular endothelial cells (hmEC aged in vitro) and their non-aged (young) counterparts was quantified. The migration of aged human microvascular endothelial cells and the effect of inhibition of TIMP1 on the migration of aged hmEC or collagen I was also measured. Relative to young mice, granulation tissue from aged mice showed less expression of collagenase and increased expression of TIMP1. In vitro, aged hmEC were deficient in MMP1 secretion (55 +/- 13% relative to young cells) and activity but showed increased expression of TIMP1 (280 +/- 109% relative to young cells). Aged hmEC migrated significantly less distance than did young hmEC over a 5-day period (59 +/- 8% relative to young cells). In the presence of a blocking antibody to TIMP1, aged hmEC showed a significant increase in the distance migrated on collagen I over a 5 day period (142 +/- 11% relative to untreated aged hmEC). We propose that deficient MMP1 activity contributes to impaired cellular movement in aged microvascular endothelial cells and that perturbations that enhance collagenase activity increase their migratory ability and angiogenic potential.

Expression of capillary basement membrane components during sequential phases of wound angiogenesis.

Before capillaries sprout to form new vessels in a wound, the endothelial cells are sequestered from the surrounding stromal or provisional matrix by a well organized protein envelope called the basement membrane (BM). After breaching the BM, endothelial cells are exposed to the wound provisional matrix and begin to migrate and proliferate. Endothelial derived basement membrane proteins and molecules of the provisional matrix are mutually accessible to the endothelial cell surface during migration. Eventually, new capillaries again segregate in a formed envelope of basement membrane and resume a tubular morphology. Endothelial cell recognition of the architecture and concentration of basement membrane ligands appears to be an important determinant of capillary morphology during angiogenesis. In this study, we characterized the molecular composition, expression and steady-state transcript levels of BM proteins during sequential stages of wound angiogenesis. Specific analysis of rat capillary BM transcripts was achieved by employing a space-filling wound model which did not have non-capillary BM. Invading capillaries appeared between days 3 and 5 and matured by day 12. Occasionally, vessels larger than capillaries were observed to form by a process resembling vasculogenesis. Steady-state transcript levels for subunits of all major BM proteins studied were readily measured by day 3, and laminin and type IV collagen immunostaining were evident at the periphery of all vessels studied. From vessel initiation to regression, the transcript levels most changed were the alpha 1 and alpha 2 transcripts of type IV collagen; after an early peak, they exhibited a sharp three-fold decline as the response progressed. Conversely, entactin and laminin subunits did not decline as the response progressed, suggesting an increasing ratio of expression relative to type IV collagen. Perlecan expression was inconsistent, but it appeared to decline during the late phase of the response. Laminin beta 1 and gamma 1, but not alpha 1 or beta 2, transcripts were expressed by forming capillaries, providing evidence that the laminin 1, 3, 4 and 7 isotypes are not expressed by growing capillaries. These results also demonstrate that the steady-state ratios of type IV collagen transcripts to laminin and entactin transcripts are greatest during the early proliferative-migratory phase of angiogenesis but decrease significantly in later phases, when vessel maturation and tube formation predominate.