Cancer cell cannibalism and the SASP: Ripples in the murky waters of tumor dormancy

Abstract

Relapse in cancer patients following an apparent cure and a prolonged latency period, known as tumor dormancy, remains an unrelenting clinical crisis. Here, I expand on our recent findings that potentially link cancer cell cannibalism of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to the senescence-associated secretory phenotype (SASP) and tumor dormancy. One mysterious feature of breast cancer is that it can reemerge abruptly many years after apparent eradication of the primary tumor. The asymptomatic latency period that precedes clinical relapse is best explained by the phenomenon known as tumor dormancy, a divergent stage of tumor progression in which residual growth-arrested solitary cancer cells or small cell clusters linger somewhere in the body for an unpredictable amount of time.1 Deciphering the causal basis of tumor dormancy therefore has important therapeutic significance.It is well established that non-malignant cell types of the tumor-associated stroma profoundly influence the behavior of breast cancer cells (BCCs).2 Given that breast cancer preferentially relapses in bone, recent emphasis has been placed on uncovering the role of bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) in tumor dormancy.2 BMMSCs and BCCs readily interact once disseminated cancer cells enter the bone marrow or after MSCs are recruited into primary tumors. 2 We recently focused on these cellular interactions using a 3-dimensional (3D) tumor niche model that, due to the high cell-to-medium ratio, creates hostile conditions such as low pH and nutritional deficits characteristic of overcrowded developing tumors with vascular limitations. We discovered that human BCCs under duress in 3D cultures enter dormancy after internalizing and degrading (i.e., cannibalizing) human BM-MSCs (Fig.

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

“…In the present study, paired differential expression analysis demonstrated that dormant tumours continue to change under long-term treatment. Some of the identified dormancy-related pathways such as cell cycle arrest and senescence have established roles in metastasis dormancy [38], further supporting the relevance of our clinical model, with the senescence-associated secretory phenotype (SASP) recently suggested to regulate breast cancer dormancy and relapse [39]. As in short-term responsive tumours [16], ECM organization and degradation were significantly upregulated in dormant tumours.…”

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

“…In the present study, paired differential expression analysis demonstrated that dormant tumours continue to change under long-term treatment. Some of the identified dormancy-related pathways such as cell cycle arrest and senescence have established roles in metastasis dormancy [38] further supporting the relevance of our clinical model, with senescence-associated secretory phenotype (SASP) recently suggested to regulate breast cancer dormancy and relapse [39]. As in short-term responsive tumours [16], ECM organization and degradation were significantly up-regulated in dormant tumours.…”

Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting

“…Also, Hisamatsu et al reported that the young MSC secretome contains growth differentiation factor 6, which may play an important role in regulating the effects of old-MSC' SASP factors in geriatric diseases [241]. More importantly, MSCs from bone marrow can be cannibalized with other cancerous cells to promote tumor dormancy and SASP factors that contribute to the evolution of tumor recurrence [242].…”