The Secreted Protein Acidic and Rich in Cysteine (SPARC) gene plays a multifaceted role in numerous biological processes. This gene, also known as osteonectin or BM-40, is involved in regulating cellular interactions and tissue organization throughout the body. Understanding SPARC’s functions provides insights into both normal physiological events and the development of various diseases. Research into SPARC offers promising avenues for diagnostics and therapeutic interventions.
Understanding the SPARC Gene
SPARC stands for Secreted Protein Acidic and Rich in Cysteine, reflecting its biochemical composition. It is classified as a “matricellular protein,” meaning it is secreted into the extracellular space where it modulates interactions between cells and the extracellular matrix (ECM), rather than serving a primary structural role.
The gene is widely expressed across various tissues, particularly during embryonic development and in adult tissues undergoing remodeling, such as bone, healing wounds, and gut mucosa. This protein is highly conserved across different species. SPARC can bind calcium and copper ions. It interacts with several ECM components, including various types of collagen, vitronectin, albumin, and thrombospondin.
Physiological Roles of SPARC
By binding to structural proteins like collagen and vitronectin, SPARC influences cell adhesion, proliferation, migration, and differentiation. It is particularly expressed in tissues undergoing significant changes in cell-matrix contact, such as during tissue repair and embryonic development.
The protein also plays a role in regulating cell proliferation by arresting cells in the G1 phase of the cell cycle. It modifies the activity of various growth factors, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF)-2, and vascular endothelial growth factor (VEGF, which can decrease their ability to stimulate cell growth. SPARC can promote cellular differentiation.
SPARC influences normal angiogenesis, the process of new blood vessel formation. Its expression is observed in healing wounds, and studies in SPARC-null mice have shown accelerated dermal wound closure. In bone, SPARC is a noncollagenous protein of the bone matrix that is required for collagen to become calcified. Additionally, SPARC-null mice develop cataracts shortly after birth, indicating its involvement in maintaining lens transparency.
SPARC in Disease Development
SPARC exhibits a complex and often contradictory role in disease development, functioning as both a tumor suppressor and a promoter depending on the specific disease context, cell type, and surrounding microenvironment. In some cancers, SPARC acts as a tumor suppressor, with its production often reduced in many epithelial cancers. This suppressive activity has been observed in acute myeloid leukemia, neuroblastoma, colorectal, hepatocellular, lung, and ovarian cancers, where it can impede tumor progression.
Conversely, SPARC can display oncogenic properties in other tumor types, including gliomas, melanomas, and certain breast and prostate carcinomas. Elevated SPARC levels in the tumor stroma are associated with a poor prognosis in non-small cell lung cancer. It can promote the proliferation and migration of head and neck cancer cells, and its overexpression is linked to the metastatic potential of melanomas. In ovarian cancer, higher SPARC expression can promote cell proliferation, migration, invasiveness, and stemness, contributing to disease progression.
In pancreatic cancer, the role of SPARC is particularly intricate and debated. While high SPARC levels in peritumoral stromal fibroblasts have been linked to a poor prognosis, exogenous SPARC has shown an ability to suppress the growth of pancreatic cancer cells. SPARC expressed by human Pancreatic Stellate Cells can increase the invasion of pancreatic cancer cells.
SPARC is also implicated in fibrosis, a condition characterized by excessive tissue scarring. Elevated SPARC expression has been reported in fibrotic tissues of organs such as the heart, lungs, kidneys, and liver. In liver fibrosis, SPARC is overexpressed, and its downregulation has been shown to attenuate the profibrogenic response of hepatic stellate cells. For pulmonary fibrosis, SPARC is involved in its development.
In vascular diseases, SPARC plays a role in conditions like atherosclerosis. Its levels increase in atherosclerotic and calcified plaques, where it may regulate the calcification process and act as a procalcifying factor. In pulmonary hypertension, SPARC is upregulated in the pulmonary vasculature during disease development. It influences the proliferation and apoptosis of pulmonary arterial smooth muscle cells and microvascular endothelial cells, key features of pulmonary hypertension.
Translating SPARC Research
Understanding SPARC’s diverse functions and its involvement in disease development has opened avenues for practical applications in medicine. SPARC holds promise as a diagnostic or prognostic biomarker in various cancers. It can serve as a prognostic indicator for rectal, bladder, head and neck, gastric, and non-small cell lung cancers. High SPARC expression is linked to poor prognosis in ovarian cancer. The gene’s abnormal methylation patterns have also been suggested as an early diagnostic biomarker for pancreatic cancer.
Research is exploring therapeutic strategies that target SPARC, including modulating its expression or activity. Specific suppression of SPARC has demonstrated the ability to eliminate fibrotic changes in some contexts. SPARC’s ability to bind albumin is being leveraged for targeted drug delivery. Albumin-bound paclitaxel, known as Nab-paclitaxel or Abraxane, utilizes this binding to enhance drug accumulation within tumors.
Nab-paclitaxel’s interaction with SPARC can lead to increased intratumoral drug concentrations. Clinical studies are ongoing to further investigate the correlation between SPARC expression and the response to Nab-paclitaxel in various tumor types. One ongoing Phase 3 clinical trial, SPARC1507, is currently recruiting participants with advanced or metastatic biliary tract cancer to study its effects.