The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses

Abstract

Despite scientific advances in understanding the causes and treatment of human malignancy, a persistent challenge facing basic and clinical investigators is how to adequately treat primary and metastatic brain tumors.The blood-brain barrier is a physiologic obstruction to the delivery of systemic chemotherapy to the brain parenchyma and central nervous system (CNS). A number of physiologic properties make the endothelium in the CNS distinct from the vasculature found in the periphery. Recent evidence has shown that a critical aspect of this barrier is composed of xenobiotic transporters which extrude substrates from the brain into the cerebrospinal fluid and systemic circulation. These transporters also extrude drugs and toxins if they gain entry into the cytoplasm of brain endothelial cells before they enter the brain. This review highlights the properties of the blood-brain barrier, including the location, function, and relative importance of the drug transporters that maintain this barrier. Primary and metastatic brain malignancy can compromise this barrier, allowing some access of chemotherapy treatment to reach the tumor.The responsiveness of brain tumors to systemic treatment found in past clinical research is discussed, as are possible explanations as to why CNS tumors are nonetheless able to evade therapy. Finally, strategies to overcome this barrier and better deliver chemotherapy into CNS tumors are presented.Despite the dramatic advances in understanding the molecular basis for carcinogenesis and the development of new targeting agents to treat malignancies, a critical challenge that continues to face cancer researchers is overcoming the sanctuary for primary and metastatic disease found within the central nervous system (CNS). Brain metastases occur in a significant percentage of patients with common malignancies, with 5-year cumulative incidence rates of 16% in lung cancer patients, 7% of breast cancer patients, and 5% of patients with colon cancer (1). In diseases such as melanoma, the incidence of brain metastatic disease is reported to be as high as 55% (2). Autopsy studies show that in patients who die from cancer, up to 25% of them develop brain metastases (3).The incidence of brain metastatic disease is on the rise (4). This could be due to a number of factors, including earlier brain screening for CNS disease in cancers known to spread to the brain; improved and more widely available radiological techniques such as magnetic resonance imaging; and improved therapies to treat systemic disease, which are prolonging survival and, in turn, increasing the risk of developing metastases to the brain. The irony is that as our therapies are improving clinical outcomes and prolonging survival, the incidence of CNS disease is on the rise. Furthermore, primary brain malignancies are intrinsically resistant to most chemotherapies for reasons that are poorly understood. These realities demand that we better understand, and learn how to treat, CNS malignancy.This CNS sanctuary for metastatic as well...

Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma

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Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

“…In addition to these physiologic conditions of the BBB, numerous efflux transporters have been identified in the brain endothelium, including P-glycoprotein, MRP 1 to 6, BCRP, and organic anion and cation transporters. 12 Thus, the BBB is an efficient barrier against the entry of many drugs, including antitumor agents.…”

“…Extensive research has determined BCRP to be a transporter expressed on the luminal surface of the gastrointestinal tract, bile canniculi, renal tubules, maternal/fetal barrier in placentas, germ cell-blood barrier in testes and ovaries, and endothelial cells in BBB capillaries. 12 Several immunohistochemical stainings (GLUT1, P-glycoprotein, multidrug resistance protein [MRP] 1 to 6, BCRP) were well-known for evaluation of BBB characteristics. 12 And GLUT1 is selectively localized to the BBB.…”

“…12 Several immunohistochemical stainings (GLUT1, P-glycoprotein, multidrug resistance protein [MRP] 1 to 6, BCRP) were well-known for evaluation of BBB characteristics. 12 And GLUT1 is selectively localized to the BBB. 13 We, therefore, examined the status of the BBB at the sites of brain metastases in breast cancer patients according to the expression of GLUT1 and/or BCRP and investigated the correlation between the status of the BBB and the immunohistochemical profiles of brain metastases of breast cancer.…”

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

“…Current therapeutic options involving chemotherapy, surgery, and/or radiation have generally had limited efficacy in eradicating metastatic lesions (3,4). A major reason for the failure of chemotherapy is that the normal blood-brain barrier (BBB) and the resultant blood-tumor barrier (BTB) limit drug distribution to subtherapeutic levels (5,6). To overcome poor drug distribution to metastatic lesions, we report here the formulation of a small hyaluronic acid (HA) paclitaxel nanoconjugate that uses a passive targeting mechanism to increase drug distribution into the tumor interstitial space and an active targeting mechanism to improve the intracellular uptake of paclitaxel into the metastatic cancer cells.…”