Breast cancer cells frequently metastasize to bone and induce osteolytic bone destruction in patients. These metastases cause severe bone pain, high risk of fractures and hypercalcemia, and are essentially incurable and fatal. Recent studies show that breast cancer cells in bone activate osteoclastogenesis and bone resorption. However the underlying mechanism is poorly understood. This study shows that the p38 MAPK (p38) isoform MAPK11 (p38β) is expressed in breast cancer cells. By using specific small hairpin RNAs for MAPK11, we demonstrated that p38β-mediated p38 activity in breast cancer cells is responsible for breast cancer-induced osteolytic bone destruction. The addition of conditioned media from breast cancer cell lines MDA-MB-231 and MDA-MB-468, which have high expression of p38β, induced osteoclast differentiation and bone resorption. In contrast, knockdown of p38β in breast cancer cells reduced osteoclast differentiation in vitro and reduced bone destruction in severe combined immunodeficiency (SCID) mouse models. The knockdown of p38β did not affect tumor growth or survival or the ability of cancer cells to home to bone. Furthermore, our results showed that p38β upregulated the expression and secretion of monocyte chemotactic protein-1 (MCP-1) in breast cancer cells, and upregulated MCP-1 activates osteoclast differentiation and activity. This study elucidates a novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction. This study also indicates that targeting breast cancer cell p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer.
Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (25 months) and discovered that the presence of CSV + CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV + CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV + CTCs nor MycN amplification. Of note, the low number of CSV + CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV + CTCs (every 6 mL) are present in the blood samples compared to >3 CSV + CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV + CTC data in any study in a long-term longitudinal manner.
Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8+ TRM cells may have promising implications for the prevention of brain tumor recurrence.
Pediatric organ failure and transplant populations face significant risks of morbidity and mortality. The risk of organ failure itself may be disproportionately higher among pediatric oncology patients, as cancer may originate within and/or metastasize to organs and adversely affect their function. Additionally, cancer directed therapies are frequently toxic to organs and may contribute to failure. Recent reports suggest that nearly half of providers find it difficult to provide prognostic information regarding organ failure due to unknown disease trajectories. Unfortunately, there is a lack of uniform methodology in detecting the early symptoms of organ failure, which may delay diagnosis, initiation of treatment and hinder prognostic planning. There remains a wide array of outstanding scientific questions regarding organ failure in pediatrics but emerging data may change the landscape of prognostication. Liquid biopsy, in which disease biomarkers are detected in bodily fluids, offers a noninvasive alternative to tissue biopsy and may improve prompt detection of organ failure and prognostication. Here, we review potential liquid biopsy biomarkers for organ failure, which may be particularly useful among pediatric oncology patients. We synthesized information from publications obtained on PubMed, Google Scholar, clinicaltrials.gov, and Web of Science and categorized our findings based on the type of biomarker used to detect organ failure. We highlight the advantages and disadvantages specific to each type of organ failure biomarker. While much work needs to be done to advance this field and validate its applicability to pediatric cancer patients facing critical care complications, herein, we highlight promising areas for future discovery.
Tissue-resident memory T cells (TRM) specific to previously encountered pathogens have been characterized, but tumor-specific TRM cells in brain have not been reported in the literature. We discovered that T cells armed with FGL2-blocking single-chain variable fragments (T-αFGL2) are able to induce tumor-specific CD8+TRM cells, which prevent glioblastoma recurrence, a major obstacle in achieving long term survivors. These tumor-specific CD8+TRM displayed a unique highly expanded T cell receptor repertoire distinct from that found in peripheral tissues. Notably, these CD8+TRM cells could be transplanted into the brains of either immunocompetent or T cell deficient naïve mice, transforming them to become immune reactive to tumor cells. The mechanism study found T-αFGL2 therapy boosted CD69+CD8+ memory T cells population in tumor bearing brains, which depend on CXCL9/10-CXCR3 signaling. These findings are the first to show tumor-specific brain resident CD8+TRM generation via adoptive cellular treatment and may have promising implications for cancer immunotherapy.
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