Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers.

Background: Colonoscopic resection of adenomatous polyps reduces mortality from colorectal cancer, which remains the third leading cause of cancer-related deaths in the U.S. Most polyps can be removed endoscopically by cold snare resection, endoscopic mucosal resection, or endoscopic submucosal dissection. However, technically challenging polyps often require partial colectomy, which confers increased rates of morbidity and mortality. Emerging hybrid approaches such as combined endoscopic-laparoscopic techniques have been developed to manage benign, complex colonic polyps and reduce the need for surgical resection. Objective: This paper describes a novel technique of combined endoscopic and robotic-assisted transcolonic polypectomy for the management of a benign, complex colonic polyp not amenable to conventional endoscopic resection. Methods: A hybrid approach integrating endoscopic visualization via colonoscope with robotic-assisted transcolonic access was performed to achieve complete polypectomy in a patient with a technically challenging, benign colonic lesion and a past surgical history of extended right colectomy. The technique was evaluated in terms of feasibility, adequacy of resection, and operative considerations. Results: The combined endoscopic and robotic-assisted approach successfully enabled complete resection of a benign, complex colonic polyp that had previously failed endoscopic submucosal dissection. The procedure was performed without significant complications and allowed for reduced operative time and anticipated shorter recovery as compared to partial colectomy. Conclusions: This case demonstrates that combined endoscopic and robotic-assisted transcolonic polypectomy is a safe, feasible, minimally invasive alternative for select complex, benign colonic polyps. This novel technique may reduce the need for partial colectomy and associated morbidity, offering a promising option for managing challenging lesions, especially in patients with multiple comorbidities and high operative risk.

Background/Objectives: PI3K/AKT/mTOR is a key pathway in cell proliferation, metabolism, and survival. Activating PIK3CA mutations are seen in up to 20% of colorectal cancers and are associated with increased cyclo-oxygenase-2 (COX-2) expression. Recent studies demonstrated a significant survival benefit from taking low-dose aspirin, a nonselective COX inhibitor, supporting further exploration of the synergistic effects of combined PI3Kα inhibitor (inavolisib) and COX-2 inhibitor (celecoxib) therapy. Methods: The effects of celecoxib–inavolisib combination treatment were tested on human colorectal cancer cell lines and patient-derived organoid models. Experiments included cell viability and colony formation assays, immunoblotting, and immunofluorescence. Results: We found that celecoxib and inavolisib demonstrated synergy in suppressing the growth of colorectal cancer cell lines, grown in both 2D and 3D cell culture, regardless of PIK3CA mutation status. In patient-derived organoid models, while synergy was seen in both organoids, growth of the PIK3CA mutated organoid was more potently suppressed. Immunoblotting of cells after combination treatment showed decreased expression of mitogenic signaling marker p-AKT across all 2D cell lines and in both cell lines grown as 3D spheroids, as well as increased expression of apoptotic marker cPARP in four out of five 2D cell lines and in both cell lines grown as 3D spheroids. Immunofluorescence staining of organoids after combination treatment, however, showed no significant increase in expression of apoptotic marker Cas-3 nor in mitogenic marker Ki-67 in either organoid. Furthermore, an apoptosis assay performed on two cell lines showed no significant increase in Annexin V or phosphatidylserine staining. Conclusions: Celecoxib and inavolisib demonstrated synergy in suppressing the growth of both colorectal cancer cell lines and patient-derived organoids, though PIK3CA mutation status did not appear to affect drug efficacy in cell lines as it did in patient-derived organoids. Potential compensatory or resistance mechanisms might include oncogene drivers in the MAPK/ERK pathway. When compared to monotherapy, combination therapy was the only drug condition to significantly increase the percentage of apoptotic cells based on Annexin V and phosphatidylserine staining, and this effect was only seen in the PIK3CA mutated cell line. Ultimately, our findings provide preliminary support for celecoxib–inavolisib combination treatment as a rational therapeutic avenue warranting further preclinical investigation.