Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract
Alveolar soft-part sarcoma (ASPS) is a rare sarcoma that presents in the buttocks or thigh of young adults and often metastasizes to the brain. The present study examined the clinical features and morphology of brain metastatic ASPS. The case records of eight patients with brain metastatic ASPS admitted between November 2008 and March 2015 were reviewed. The relevant clinical data (including patient age and sex, neuroimaging studies, histopathological and immunohistochemical features, surgical records and follow-up reports) were collected through a review of patient records. The sex distribution was 3:1 male to female and the age ranged between 15 and 33 years at the time of surgery. In total, five patients with brain metastases had concurrent pulmonary metastases. The lesions were hypointense on T1-weighted images in every patient, hyperintense on T2-weighted images in six patients and contrast enhancement was present in all patients. The most notable immunohistochemical feature was strong immunohistochemical staining for TFE3 in each patient. Gross total resection was performed in all eight patients, with two patients undergoing adjuvant radiotherapy and one undergoing adjuvant chemotherapy. Four recurrent cases were observed during the follow-up. TFE3 staining and knowledge of its microscopic characteristics would facilitate earlier diagnosis: Early diagnosis with a multidisciplinary, multimodal approach to treatment is required to achieve extended disease-free survival in patients with brain metastatic ASPS.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661425/

Jussi supplied the above article to me as I was under the impression that there hadn’t been any reports of ASPS patients presenting with brain tumors , without having had lung tumors prior.
The above article appears to prove that wrong .


Table I, list that 3 of the 8 patients with brain mets , had no pulmonary tumors at time of brain tumor discoveries .

Results
Clinical presentation The clinical features of the eight patients in the present study are summarized in Table I. The ages of patients ranged between 15 and 33 years (mean, 25.3 years). The sex ratio was 3:1 male to female. The duration of symptoms ranged between1 and 22 weeks. Headache and scalp mass were the most common initial symptoms. The most common site of the primary tumor was in the extremities (6/8 patients, 75%), with the lower extremity being involved in 5 of these 6 patients (83.3%) and the upper extremity in one patient (16.6%). The torso was involved in two patients (25%): The chest of one patient and the abdominal region of the other. In addition, 5/8 (62.5%) patients with brain metastases had concurrent pulmonary metastases. The median preoperative KPS score was 86.3±5.2 (Table I).

February 27, 2014
Source:
Memorial Sloan Kettering Cancer Center
Summary:
The biologic mechanisms that individual cancer cells use to metastasize to the brain have been revealed by recent research. Metastasis, the process that allows some cancer cells to break off from their tumor of origin and take root in a different tissue, is the most common reason people die from cancer. Metastatic brain tumors are ten times more common than primary brain cancers. Yet most tumor cells die before they can take root in the brain, which is better protected than most organs against colonization by circulating tumor cells. To seed in the brain, a cancer cell must dislodge from its tumor of origin, enter the bloodstream, and cross densely packed blood vessels called the blood-brain barrier. Until now, little research has been done into how metastatic brain tumors develop.




https://www.sciencedaily.com/releases/2 ... 134706.htm

“New research from Memorial Sloan Kettering provides fresh insight into the biologic mechanisms that individual cancer cells use to metastasize to the brain. Published in the February 27 issue of Cell, the study found that tumor cells that reach the brain -- and successfully grow into new tumors -- hug capillaries and express specific proteins that overcome the brain's natural defense against metastatic invasion.”

Metastasis, the process that allows some cancer cells to break off from their tumor of origin and take root in a different tissue, is the most common reason people die from cancer. Metastatic brain tumors are ten times more common than primary brain cancers.

Yet most tumor cells die before they can take root in the brain, which is better protected than most organs against colonization by circulating tumor cells. To seed in the brain, a cancer cell must dislodge from its tumor of origin, enter the bloodstream, and cross densely packed blood vessels called the blood-brain barrier. Until now, little research has been done into how metastatic brain tumors develop, but previous mouse experiments that imaged metastatic breast cancer cells over time have shown that of those cancer cells that do make it to the brain, fewer than one in 1,000 survive.

"We didn't know why so many of these cells die," says Joan Massagué, PhD, Director of the Sloan Kettering Institute and senior author of the study. "What kills them? And how do occasional cells survive in this vulnerable state -- sometimes hiding out in the brain for years -- to eventually spawn new tumors? What keeps these rare cells alive and where do they hide?"

In the Cell study, Dr. Massagué, with Fellow Manuel Valiente, PhD, and other team members, found that in mouse models of breast and lung cancer -- two tumor types that often spread to the brain -- many cancer cells that enter the brain are killed by astrocytes. These killer cells, the most common type of brain cell, secrete a protein called Fas ligand.

When cancer cells encounter this protein, they are triggered to self-destruct. The exceptional cancer cells that escape the astrocytes do so by producing a protein called Serpin, which acts as a sort of antidote to the death signals fired at them by nearby astrocytes.

After imaging defiant metastatic cells in the brains of mice, researchers noticed that the cells that were able to survive grew on top of blood capillaries, each cell sticking closely to its vessel "like a panda bear hugging a tree trunk," Dr. Massagué says. They found that the tumor cells produce a protein that acts like Velcro to attach the cells to the outer wall of a blood vessel.

"This hugging is clearly essential," Dr. Massagué explains. "If a tumor cell detaches from its vessel, it gets killed by nearby astrocytes. By staying on, it gets nourished and protected, and may eventually start dividing to form a sheath around the vessel."

Under the microscope, the researchers watched these sheaths of cancer cells around the blood capillaries grow into tiny balls, which eventually became tumors. "Once you've seen it, you can never forget this image," Dr. Massagué says.

The brain appears to have exceptional defenses beyond the blood-brain barrier against cancer cell colonization. Valiente et al. searched for factors that enable some types of cancers to establish metastases in the brain in the transcriptome of brain-metastatic (BrM) subpopulations of lung (H2030 and PC) and breast (MDA-MB-231 and CN34) cancer cell lines. Compared with parental cells, bone- or lung-metastatic subpopulations of MDA-MB-231 cells, the BrM subpopulation showed increased mRNA abundance for at least one of four genes encoding the serpin family of protease inhibitors. BrM cells had increased protein abundance of serpins B2 and I1 (also known as neuroserpin), which inhibit plasminogen activator (which converts plasminogen to plasmin), and SERPINB2 and SERPINI1 expression were associated with brain metastasis in human primary lung adenocarcinomas. After intracardiac injection in mice or seeding onto brain slices, parental H2030 cells had a high rate of apoptosis in brain tissue, whereas BrM-H2030 cells bound, coated, and proliferated along the abluminal surface of brain capillaries. The only serpin that was more abundant in BrM-H2030 cells than in parental cells was neuroserpin, and knockdown of SERPINI1 did not affect cell proliferation in culture but inhibited metastasis in mice and colonization (and increased apoptosis) in brain slices. In BrM-PC9 cells injected into mice, overexpression of wild-type neuroserpin, but not a catalytically inactive form, promoted brain but not bone metastasis. Plasmin cleaves the cytokine FasL, which activates apoptosis through the adaptor protein FADD.

http://stke.sciencemag.org/content/7/317/ec72

Plasmin cleaves the cytokine FasL, which activates apoptosis through the adaptor protein FADD. FasL was enriched in reactive astrocytes in BrM-H2030–derived brain metastatic lesions in mice. Addition of neuroserpin or serpin B2 decreased the amount of soluble FasL in mouse brain slices, indicating that serpins inhibit the production of FasL. However, although inhibition of FasL signaling through a dominant-negative FADD blocked apoptosis in neuroserpin-deficient BrM-H2030 cells, it did not restore their metastatic capacity. Plasmin also cleaves L1CAM, a cell adhesion protein that is associated with cell invasion and poor prognosis in various cancers. L1CAM was abundant in brain metastasis samples from nonsmall-cell lung cancer patients and was concentrated at the interfaces between BrM-H2030 cells and capillaries, as well as between adjacent BrM-H2030 cells in brain lesions in mice. L1CAM knockdown prevented BrM-H2030 and BrM-MDA-MB-231 cells from spreading and proliferating over capillaries in mouse brain slices and prevented the metastasis of neuroserpin-overexpressing BrM-PC9 cells. Addition of plasmin to cultured BrM-H2030 cells decreased the surface abundance of L1CAM as well as their cell adhesion capacity. Together, these findings suggest that targeting serpins in lung and breast cancer cells may prevent brain metastasis.