Abstract
Cancer-initiating cells (CIC) account for metastatic spread, which may rely mostly on CIC exosomes (TEX) that affect host cells and can transfer CIC features into Non-CIC. The CIC marker CD44 variant isoform v6 (CD44v6) being known for metastasis-promotion, we elaborated in cells its contribution to migration and invasion and in TEX the tranfer of migratory and invasive capacity to Non-CIC, using a CD44v6 knockdown (CD44v6kd) as Non-CIC model.A CD44v6kd in human pancreatic and colorectal cancer (PaCa, CoCa) lines led to loss of CIC characteristics including downregulation of additional CIC markers, particularly Tspan8. This aggravated the loss of CD44v6-promoted motility and invasion. Loss of motility relies on the distorted cooperation of CD44v6 and Tspan8 with associated integrins and loss of invasiveness on reduced protease expression. These deficits, transferred into TEX, severely altered the CD44v6kd-TEX composition. As a consequence, unlike the CIC-TEX, CD44v6kd TEX were not taken up by CD44v6kd cells and CIC. The uptake of CIC-TEX was accompanied by partial correction of CIC marker and protease expression in CD44v6kd cells, which regained migratory, invasive and metastatic competence. CIC-TEX also fostered angiogenesis and expansion of myeloid cells, likely due to a direct impact of CIC-TEX on the host, which could be supported by reprogrammed CD44v6kd cells.Taken together, the striking loss of tumor progression by a CD44v6kd relies on the capacity of CD44v6 to cooperate with associating integrins and proteases and its promotion of additional CIC marker expression. The defects by a CD44v6kd are efficiently corrected upon CIC-TEX uptake.
Highlights
Cancer related mortality is mostly du to metastatic spread [1, 2]
A higher percentage of CD44v6kd than wt cells is in G2/M, whereas a higher percentage of Capan1 spheres and A818.4 and SW480 holoclones are in G0, indicating the more rapid progression of CD44v6kd cells through the cell cycle and the more resting state of cancer initiating cells (CIC)-enriched populations (Figure 1E, Supplementary Figure 1D)
Upregulated expression of MMP2 and MMP9 may support invasiveness of the motile tumor cells. (ii) CD44 variant isoform v6 (CD44v6) is engaged in apoptosis resistance, frequently via activation of antiapoptotic pathways or by stabilizing drug resistance [27]
Summary
Cancer related mortality is mostly du to metastatic spread [1, 2]. One of the first steps in the metastatic cascade is the emigration of individual tumor cells out of the primary tumor mass [3]. There is evidence that the subpopulation of cancer initiating cells (CIC) accounts for tumorigenicity, tumor recurrence and metastasis [4, 5]. CIC can be enriched by their capacity to grow as spheres or holoclones, which are supposed to reflect self renewal capacity (5a, 5b). Tightly packed cells, meroclones contain larger, loosely attached transit cells and paraclones, large, flattened differentiating cells [6, 7]. CIC are defined by their markers [8], CD44v6 being a CIC marker in pancreatic and colorectal adenocarcinoma (PaCa, CoCa) [9,10,11,12,13]
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