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Page 2 of 13 Eng et al. J Cancer Metastasis Treat 2019;5:69 I http://dx.doi.org/10.20517/2394-4722.2019.021

current knowledge gap in understanding the metastatic process, which impacts our ability to offer curative
treatment options to cancer patients.

In the early stages of cancer, tumors are typically benign and remain confined within the normal
boundaries of a tissue. As tumors grow and become malignant, however, they acquire the capacity to break
through these boundaries and invade adjoining tissues. Notably, dissemination of tumor cells can occur
[2]
relatively early in cancer progression . During the process of metastasis, only a rare population of invasive
cancer cells escape the primary tumor, survive the treacherous transit through the circulatory system,
[3]
and subsequently establish secondary tumors in distant organs/tissues . These invasive cancer cells,
which exhibit extensive cytoskeletal remodeling, secrete proteases like extracellular-matrix-degrading
metalloproteinases and cathepsins to drive their invasion and migration through the stroma, a network
[4,5]
of supportive, connective tissue cells at the basement membrane . Furthermore, the stroma can actively
promote the initiation of metastasis by releasing transforming growth factor-β and other cell-signalling
proteins to trigger cancer cells to undergo epithelial-to-mesenchymal transition (EMT) - a reversible
phenotypic change in which cells lose intercellular adhesion and epithelial polarization and gain motility
and invasiveness . Transition into a mesenchymal cancer cell state allows for efficient intravasation of
[6]
the lymphovascular system and acquisition of a stem-cell phenotype to promote survival during transit.
These circulatory cancer cells can be arrested at distant organs/tissues, where they extravasate into the
parenchyma of target organs to commence colonization. After extravasation, the invading cancer cells
undergo mesenchymal-to-epithelial transition (MET) at the new settlement sites. The conduciveness
of these niches for colonization can dictate the period of dormancy of these micrometastatic cancer
cells. Long period of latency often exists between the development of a primary tumor and clinical
manifestations of metastasis, indicating that metastatic colonization is a highly inefficient process in
which most of these disseminated tumor cells (DTCs) die. To survive and establish macrometastases at
distant organs/tissues, the minor subset of DTCs must overcome immune surveillance and other host-
[7]
tissue defenses to achieve overt colonization at secondary sites . Although breast-to-lung metastases have
[8]
been shown to arise mainly from cells that have not undergone EMT in mouse models of breast cancer ,
it could be interpreted as rapid conversion into the epithelial cell state of DTCs, via MET, as soon as they
arrive at supportive niches in the lung. Notably, the breast cancer cells that have undergone EMT are
found to be resistant to chemotherapy and this could be attributed to their acquisition of a stem cell-like
[9]
phenotype .

AUTOPHAGY: A CRUCIAL CANCER CELL SURVIVAL MECHANISM DURING METASTASIS
Autophagy is a cellular housekeeping mechanism which degrades and recycles bulks of cytoplasmic
[10]
materials for the synthesis of essential cellular components . Highly conserved from yeast to mammals,
autophagy acts as an adaptive response to environmental stresses such as nutrient deprivation. The
autophagy machinery has multiple distinct stages: initiation, nucleation, elongation, fusion and cargo
[10]
recycling . During stress, shifts in nutrient availability can be detected by proteins involved in energy
[11]
homeostasis, such as the 5’ AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1
(TORC1). The activation of AMPK and the corresponding inhibition of TORC1 will lead to the assembly of
the Atg1/ULK complex, thereby kickstarting autophagy.

During autophagy, cytoplasmic cargoes are encapsulated by double-membrane vesicles known as
autophagosomes and thereafter sent to the lysosomes to be degraded . The intricate, multistep processes
[12]
of autophagy are facilitated by numerous autophagy-related proteins (Atg). Detailed characterization of
these proteins can be found in the review by Feng et al. . At the initiation stage, the Atg1/ULK complex
[13]
is assembled. This complex consists of Atg1/ULK, the regulatory subunit Atg13 and the scaffold complex
Atg7-Atg31-Atg29 [Figure 1]. Importantly, the assembly of the Atg1/ULK complex is critical for the