Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

Abstract

The majority of cancer deaths can be attributed to cancer cell metastases that migrate to distant target organs. Brain metastases constitute one of the leading causes of morbidity and mortality among cancer patients, occurring in about 40% of patients with metastatic disease. Thus, there exists an unmet need for early detection, diagnosis, and treatment directed against early stage cancer cell metastasis. Previous studies have reported the development of methods to detect and identify early circulating tumor cells (CTCs) in the bloodstream prior to their seeding into distant organs. Using a comprehensive analysis of total CTCs mRNA content, investigators have developed a mRNA "transcriptome signature" of 126 genes involved in CTC metastatic events. The genes were parsed into various metastatic-related activities indicating that CTCs sustained a semi-dormancy state bent on: (1) stress survival; (2) metabolic maintenance; (3) DNA and translational stability; and (4) chemotactic pro-inflammatory capabilities. These activities suggested that CTCs might be susceptible to interactions with protein-derived peptide segments whose actions are involved with metastatic activities such as cell invasiveness, contact, adhesion, motility, spreading, and migration. The use of proteinderived (encrypted) peptides to impede CTC metabolic activities and disrupt signaling pathways could have therapeutic potential in patients with early metastatic disease.

Alpha-Fetoprotein-derived Segments as Integrin Peptidomimetics for Potential Cancer Cell Targeting and Therapy: A Review and Commentary

“…In addition, ILPs such as GIP have been reported to induce apoptosis in radio-sensitized cultured lymphocytes [33]. Moreover, it has been reported that ADAM-22, a disintegrinlike metalloproteinase, is an active participant in the development of breast cancer resistance during endocrine hormone therapy in women [48][49][50]. With regard to this report, GIP administered to cultured MCF-7 human breast cancer cells was shown to down-regulate the expression of ADAM-22 by 30-fold as determined by a global RNA microarray analysis [44].…”

Peptide therapeutics in the management of metastatic cancers

“…This GIP fragment has been chemically synthesized and has growth inhibiting and anti-metastatic properties. 124 …”

“…This GIP fragment has been chemically synthesized and has growth inhibiting and anti-metastatic properties. 124 The somatostatin peptide (SST) binds its receptor (SSTR) thereby inhibiting proliferation and inducing apoptosis of cells. 125 The SST peptide has a nominal half-life of only about 3 minutes in plasma.…”

Breast cancer, metastasis, and the microenvironment: disabling the tumor cell-to-stroma communication network

“…There exists an extensive reserve of natural protein-derived peptide segments encrypted within the polypeptide structure of circulating blood proteins and ECM/interstitial cell-secreted proteins [31,32] . The proteome of both humans and other mammals contain precursors and preproteins that when cleaved by proteolysis, release peptide fragments with diverse biological activities.…”

“…GHRH: growth hormone releasing hormone; TRH: thyroid releasing hormone; GIP: growth inhibitory peptide; TSH: thyrotrophin stimulating hormone or carboxy-terminal ends of various proteins, while others can be exposed following a conformational change in the proteins' tertiary structure. Such a conformational change in a protein can be induced by environmental events such as stress, shock, oxidative state changes, osmotic pressure, pH, and high ligand concentrations [31,32] . Once identified in nature, single peptide fragments can be synthesized in the laboratory.…”