Autophagy is a stress-induced cell survival program whereby cells under metabolic, proteotoxic, or other stress remove dysfunctional organelles and/or misfolded/polyubiquitylated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. The end result is the release of free amino acids and metabolites for use in cell survival. For tumor cells, autophagy is a double-edged sword: autophagy genes are frequently mono-allelically deleted, silenced, or mutated in human tumors, resulting in an environment of increased oxidative stress that is conducive to DNA damage, genomic instability, and tumor progression. As such, autophagy is tumor suppressive. In contrast, it is important to note that although tumor cells have reduced levels of autophagy, they do not eliminate this pathway completely. Furthermore, the exposure of tumor cells to an environment of increased metabolic and other stresses renders them reliant on basal autophagy for survival. Therefore, autophagy inhibition is an active avenue for the identification of novel anti-cancer therapies. Not surprisingly, the field of autophagy and cancer has experienced an explosion of research in the past 10 years. This review covers the basic mechanisms of autophagy, discusses its role in tumor suppression and cancer therapy, and posits emerging questions for the future.

Context.— Despite continued surveillance and intravesical therapy, a significant subset of patients with lamina propria–invasive bladder cancer (T1) will progress to muscle-invasive disease or metastases. Objective.— To analyze the value of pathologic subcategorization of T1 disease in predicting progression. Design.— Six substaging methods were applied to a retrospective cohort of 73 patients, with pT1 urothelial carcinoma diagnosed on biopsy/transurethral resection. Additionally, the immunohistochemistry for GATA3 and cytokeratin 5/6 (CK5/6) was performed to study the prognostic value of stratifying T1 cancers into luminal or basal phenotypes. Results.— On follow-up (mean, 46 months), 21 (29%) experienced at least 1 recurrence without progression, and 16 (22%) had progression to muscle-invasive disease and/or distant metastasis. No differences were noted between progressors and nonprogressors with regard to sex, age, treatment status, medical history, tumor grade, and presence of carcinoma in situ. Substaging using depth of invasion (cutoff ≥1.4 mm), largest invasive focus (≥3.6 mm), aggregate linear length of invasion (≥8.9 mm), and number of invasive foci (≥3 foci) correlated significantly with progression and reduced progression-free survival, whereas invasion into muscularis mucosa or vascular plexus, or focal versus extensive invasion (focal when ≤2 foci, each <1 mm) failed. Patients with luminal tumors had higher incidence of progression than those with nonluminal tumors (27% versus 11%), although the difference was statistically insignificant (P = .14). Conclusions.— Substaging of T1 bladder cancers should be attempted in pathology reports. Quantifying the number of invasive foci (≥3) and/or measuring the largest contiguous focus of invasive carcinoma (≥3.6 mm) are practical tools for prognostic substaging of T1 cancers.

Dense tumor innervation is associated with enhanced cancer progression and poor prognosis. We observed innervation in breast, prostate, pancreatic, lung, liver, ovarian, and colon cancers. Defining innervation in high-grade serous ovarian carcinoma (HGSOC) was a focus since sensory innervation was observed whereas the normal tissue contains predominantly sympathetic input. The origin, specific nerve type, and the mechanisms promoting innervation and driving nerve-cancer cell communications in ovarian cancer remain largely unknown. The technique of neuro-tracing enhances the study of tumor innervation by offering a means for identification and mapping of nerve sources that may directly and indirectly affect the tumor microenvironment. Here, we establish a murine model of HGSOC and utilize image-guided microinjections of retrograde neuro-tracer to label tumor-infiltrating peripheral neurons, mapping their source and circuitry. We show that regional sensory neurons innervate HGSOC tumors. Interestingly, the axons within the tumor trace back to local dorsal root ganglia as well as jugular–nodose ganglia. Further manipulations of these tumor projecting neurons may define the neuronal contributions in tumor growth, invasion, metastasis, and responses to therapeutics.

Patients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve recruitment has not been tested. Using a murine model of ovarian cancer, we show that tumor-infiltrating sensory nerves potentiate tumor growth, decrease survival, and contribute to treatment resistance. Furthermore, matched patient samples show significantly increased tumor innervation following chemotherapy. In vitro analysis of tumor-released extracellular vesicles (sEVs) shows they harbor neurite outgrowth activity. These data suggest that chemotherapy may alter sEV cargo, endowing it with robust nerve recruiting capacity.

INTRODUCTION: Synovial sarcoma (SS) is an uncommon subtype of mesenchymal derived solid tumors that is characterized by its unique histologic pattern. It is most often found in the extremities and rarely, the digestive tract, which can lead to gastrointestinal bleeding. Gastric tumors of mesenchymal origin often have overlapping radiographic and endoscopic appearances, which presents a significant challenge in diagnosis. We report one of only 3 confirmed cases of primary gastric synovial sarcoma of the lesser curvature in a patient who presented with hematemesis. CASE DESCRIPTION/METHODS: A 26-year-old male presented with a two-week history of worsening abdominal pain and intermittent hematemesis. He denied any history of hematochezia, melena, early satiety, weight loss, recent NSAID use or alcohol ingestion. Exam was notable for epigastric tenderness without rebound or guarding. Labs revealed microcytic anemia and thrombocytopenia without transaminitis or elevated lipase. Abdominal CT showed an 8 cm mass along the posterior gastric body with suspicion for intratumoral hemorrhage, highly suggestive of a gastrointestinal stromal tumor (GIST) [Figure 1]. EGD revealed a large, ulcerated, non-bleeding, non-circumferential, submucosal mass on the lesser curvature of the stomach, also concerning for a GIST [Figure 2]. Endoscopic ultrasound showed neither hepatic invasion nor lymphadenopathy. Partial gastrectomy pathology supported the endoscopic biopsy results, which showed high grade, monophasic, atypical spindle cells with t(X;18)(SYT-SSX) chromosomal translocation by fluorescence in situ hybridization (FISH). Immunohistochemistry (IHC) was strongly positive for TLE1 staining, but negative for C-KIT and DOG-1, to which GISTs are immunoreactive, confirming a diagnosis of primary gastric synovial sarcoma [Figure 3]. He tolerated 6 cycles of sarcoma-directed chemotherapy without evidence of progressive disease. DISCUSSION: Intramural gastric spindle cell malignancies are difficult to distinguish from one another, and require different disease-tailored therapies. Though GISTs account for 90% of these tumors, other rare pathologies exist. These include synovial sarcomas, which are characterized by a variable degree of epithelial differentiation associated with a disease-specific gene translocation. In patients with hematemesis found to have endoscopic and radiographic findings suspicious for GIST, ICH and FISH analyses are crucial to differentiate between mesenchymal malignancies to guide effective therapy.