Cytocapsular tubes and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis

Abstract

AbstractCancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer lethality. Cytocapsular tubes (CCTs) and their networks are physical membrane-enclosed freeway systems for cancer cell dissemination across tissues and organs in vivo. Whether cytocapsular tube superlarge biomembranes function as superdenfence and conduct cdp-rtm is unknown. It is also unknown whether conventional cancer drug development methods, including cancer cell line derived xenograft (CDX) and patient cancer cell derived xenograft (PDX), generate cytocapsular tubes (CCTs). It is also unclear whether xenografts can be created that contain CCTs for efficient cancer drug development. Here, we investigated CCT functions related to cancer drug resistance, CCTs in CDX and PDX and CCT xenograft (CCTX). Using clinical cancer tissues, we discovered that CCTs potently shielded against multiple chemotherapy treatments with diverse conventional cancer drugs. Next, our quantitative analyses show that CCT biomembrane drug barriers significantly increase cancer drug resistance by 6.6-folds to14-folds. We found that conventional CDX and PDX animal models do not generate CCTs in these xenografts. By mimicking in vivo cancer cell environments for cancer patient cancer cell culturing, we have successfully isolated CH-5high/CH-6high subpopulations of patient breast cancer cells and pancreas cancer cells that are propertied with cytocapsular tube generation capacities and engender large quantities of CCTs in mouse xenografts. Biochemical and immunohistochemistry analyses demonstrated that CCTs in these xenografts are similar to those in clinical cancer tissues. In summary, our research has identified that CCTs and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis, and developed a CCTX platform for highly efficient cancer drug development, which pave avenues for more efficient development of effective and precise cancer drugs for tumor cure at both personal and broad-spectrum levels.