The organism is made of cells.   Cells aggregate into tissues units, that assemble into tissues.  Several tissues make an organ, Nearly all cells live less than the organism does. Epithelia in the gut live two days, skin cells, three weeks. Red blood cells live 120 days, and bone cells, several years.  Dying cells are replaced with newly formed cells, a process known as cell turnover.

The entire surface of our skin, known as epidermis, is replaced every three weeks. Skin cell population consists of young , adult and old cells. Just like the human population. One would assume that once a cell is formed it will stay in the place of it birth. Eventually  die there, and replaced by a new cell. Yet this is not the case. Cells in the body are formed at one place and literally stream to their graveyard.

Tissue unit

During  growth, organism does not pile up cells like bricks. Its building blocks consist of cell clusters, called tissue units.
The tissue unit is made of five components, embedded in a gel matrix:

-Epithelium cells
-Connective tissue
-Nerve fibers
-Blood vessel
-Lymph vessel

Epithelium cells are responsible for tasks executed by the unit.. Connective tissue cells contribute the scaffold and matrix. Nerve fibers provide communication with other units. Resources arecarried by blood carrying vessels. Lymph vessels  drain tissue fluid  to other units.  

Epithelium cell kinetics   

The tasks of each unit are carried out by epithelium, which supported by the remaining components. There are two types of epithelia: Progenitors, that divide, and  non-dividing end-cells.. Progenitors like end-cells, perform many metabolic functions, they differ from end-cells in their capability to produce new cells. The cell at unit origin is called, Determined Stem Cell (DS), Its more distant neighbor, is the Committed Stem Cell (CS).

The scheme depicts an instantaneous picture of a unit in flux, directed from origin to periphery. In order to appreciate it better let us follow a  DS  at two time points:  t₁  and t₂ , like now and in one hour. Now DS is a single cell, and  at t₂ (next hour) it divides into two cells. One offspring replaces the parent and remains a DS, while the other becomes a CS which has to be placed beside the DS.  In order to enter its new location, all remote cells move outward and vacate it. Thus, each progenitor cell division is accompanied by an outward steaming of all remote cells. Cell streaming is linked with cell division, When progenitors divide rapidly, remote cells travel faster, and vice versa. Cell flux and turnover are linked.     

All cells except the DS continually stream outward. Since during each DS division one offspring replaces the parent cell, DS keeps its position at origin. Other cells stream while dividing. Upon arriving at unit end, they die. Thus all cells except DS, are called transitional cells and are short lived..        

CS is the first transitional cell formed in the unit. As it streams it ages, and its appearance changes.  First turning into an amplifying progenitor, "Amplifying" indicates that by repeated cell division these cells increase  the unit cell content. Further down along the cell stream, a progenitor stops dividing , turning into  an end-cell, and when reaching unit periphery, it dies. This change of the cell is called differentiation. In other words, as cells stream, they age and differentiate.

All cells in a tissue unit are descendants of one DS, belonging to one cell clone. The tissue unit is therefore mono-clonal. Destroy the DS and the entire unit gradually dies. It may live as long as transitional cells do. As they approach periphery, the unit gradually dwindles away. 

In the gut epithelium, a differentiating  CS  lives two days. In the skin (epidermis) it lives three weeks. Cell streaming was described nearly in all epithelia of the organism, e.g. gut,, skin liver, pancreas, salivary glands, adrenal and kidney. The list of relevant publication is given below.We may safely assume that wherever cells divide their turnover is structured in the same way. All cells except heart cells, divide, and turn over. With the discovery of dividing DS in the brain, even this organ turns over, and divided into tissue units, that are structured in the same fashion as our simplified scheme. 

Not all units are so obvious like thos of the skin or gut. Bone marrow cells are dispersed and it is difficult to imagine that they  follow the above scheme. Yet they do. Each cell carries a unique marker represented here by its color.  They may be sorted and arranged along a row exactly like skin epithelium..Mathematically this observation may expressed as follows. Since DS generates  the entire unit. The various differentiation states of cells may be defined by continuous transformations. All tissue units are homeo-morphic.

Tissue unit behavior may now be summarized by several rules:
1.    The unit is generated by its DS.
2.    Cells stream from their birth site to their graveyard.
3.    Velocity is proportional to cell division rate.

Embryogenesis

While a cell is the basic unit of the organism, tissue unit is its basic building block.  Our existence starts as a fertilized ovum, or zygote,  our primordial stem cell. Its nucleus contains a blueprint of the organism. A set of directives that will serve for constructing it. Initially zygote is nourished by maternal fluids of the womb. Resources enter the cell by diffusion. It rapidly divides into a cell cluster, called morula. Since outer cells are first to get their needs, less is left for inner cells. In order to get their needs they have to push their way outward. The cluster turns into a balloon filled with fluid, called blastocyst. Its skin is made of a single cell layer. All cells get their needs and non is deprived anymore. 

 In the following developmental stage, called gastrula, some cells fold into the balloon creating a small gut. Other cells form an inner layer. They cannot rely anymore on getting resources by diffusion, and have to grow their own vascular supply. This is achieved by creating tissue units with the five ingredients mentioned above.     

From now on embryo grows in a similar way as growing cities, by adding quarters. Each tissue unit is like a city quarter. Its buildings are cells and its infrastructure, vessels and nerve fibers,. Yet unlike real quarters, the unit is oriented. A stem cell at its origin generates the entire unit. Its progeny, the transitional cells stream to their graveyard.   

Whenever a new unit is created, a stem cell buds off its parent. In an adult that stopped growing, a dividing DS generates two different progeny, a DS and a CS, which is called asymmetric stem cell division. In the growing embryo, prior to forming a new unit the DS divides  into two DS , one maintains the old unit, while the other generates a new one. This is known as symmetric stem cell division. 

The figure depicts a unit at four time points:
1.    Parent unit
2.    DS divides symmetrically creating a bud.
3.    Unit elongates to a 4-cell stage.
4.    Unit elongates to a 8-cell state.

Proliferon 

Actually, unit budding is somewhat more complicated.  When an epithelial DS buds off its parent unit, it is joined up by a connective tissue DS. Both get a supply of budding vessels, and nerve fibers. As the unit elongates, its vessels and nerve fibers  also elongate, reminding of how new city quarters expand. This complex vas called Proliferon  
.

The scheme is an instantaneous image of a streaming proliferon. An asymmetric epithelial DS division is accompanied by an asymmetric connective tissue DS division. The two CS cells, start their voyage together, accompanied  by their infra-structure. Thus each DS  division creates a proliferon quantum that moves outward. In the urban context, formation of a CS is like building a new house with its pipes and cables. Here, the  house  gradually moves to the quarter periphery whereupon it is demolished. Not only cells are being renewed, but vessels and nerve fibers as well.

In order to simplify the discussion, we shall concentrate on epithelial cells, keeping in mind the proliferon.     

Panta Rhe (All streams)

Heraclitus once said: "All streams"  (panta rhe). And added:" you never step into the same river twice", To which we may now add, you never meet the same individual twice, since all  his cells stream.

Tissue unit as JAVA program.

Zygote is the top most class in the organism. It is the root of the system. DS cells are its subclasses. Transitional cells are objects generated by DS. An asymmetric  DS division instantiates an object.  When reaching tissue periphery,  object  dies and is cleared  by the garbage collector. DS class inherits its properties from the zygote class. All DS cells in a given tissue belong to a package. A symmetric DS division, is equivalent to the formation of a new class. Since tissue packages  differ from each other, their classes hide some variables, and override some methods inherited from zygote. Household cell functions are methods that cannot be overridden. Runtime environment emerges.    

Neoplastic progression

Cancer is a systemic disease manifested by three features:        
1. Cachexia, or body wasting.
2. Para-neoplasia, manifested by hormonal dysfunction and nerve conduction disturbances.
3. Neoplasia, the tumor. 

We shall restrict our discussion to tumors made of epithelial cells. When treating laboratory animals with carcinogens, tumor evolution can be studied from its very beginning. Most of the information described here was gathered in mice and rats intestinal epithelium treated with carcinogens. 
        
A tumor is initiated in a single tissue unit. A normal cell is transformed into a neoplastic.  Obviously this transformed cell has to be a DS, since transformed  transitional cells are soon washed out of the unit. Tumor initiation is a stem cell event.  Tumor, like other tissues, grows by addition of proliferons. The image depicts two stages of tumor formation , starting with a healthy unit.

1 There are more progenitors and less end-cells.
2 The above changes intensify. In addition, unit elongates, DS cells bud off, and create new units.

Since progenitors become more abundant, more cells divide, their turnover rises, and cell streaming accelerates. End-cell depletion, is known as Maturation Arrest. The unit is less mature. With time these changes intensify, and unit elongates. Gradually more and more new units appear.        

 
These are the earliest changes in neoplastic (or tumor) evolution. They are called also precursor lesions, exhibiting the salient features of a tumor. Progenitor amplification. Particularly increased stem cell abundance.  In the gut it takes about five years, until a full fledged neoplasm is detected.     

During evolution, tumor-proliferon changes its appearance. It grows in size, multiplies its units, and becomes more and more immature. Tasks that were hitherto performed by mature epithelia, are canceled (maturation arrest), and replaced with new ones, that are now performed by progenitors. It has to be stressed that progenitors like end-cells, perform many metabolic functions.

Tumor

Tumor is an organ with a new purpose, that evolves like an embryo by proliferon addition.  Generally DS cells are close to  vessels from which the budding proliferon draws its infra-structure.  Due to its polarity, the unit points away from adjacent vessels. Its origin rests near a vessel and its periphery points away from it. As more units are added they  form a lump covered with a capsule through which vessels pass. Units whose  origins are a placed below the capsule point to the tumor  center. Since transitional cell stream inward where they die. Dead tumor cells accumulate in the  center.

As disease advances, DS cells enter adjacent vessels and travel to other tissues, where they bud into proliferons called metastases.

Chemotherapy        

A tumor grows in the same way as an embryo. Its transitional cells are short lived, continually streaming to their graveyards. Chemotherapy generally inhibits cell formation As transitional cells continue dying,  in the absence of new cells,  tumor shrinks. DS are spared, since resisting the poison. When chemotherapy is stopped, they replenish their proliferons with transitional cells, and tumor grows  again.  With repeated chemotherapy treatments, DS number rises so that the entire tumor is made of DS (anaplasia),  and resists chemotherapy.

Chemotherapy generally fails since enriching resistant DS (clonogenic cells). Neoplastic DS resist chemotherapy in the same way as normal DS do. One might raise the amount of poison and eliminate neoplastic DS, yet this would destroy also all other DS and kill the patient. Since chemotherapy fails to eliminate the tumor, it should be given solely for alleviating tumor induced damage. Imagine a tumor  that obstructs airways, and his size has to be reduced. Treatment will be helpful if tumor is made mainly from transitional cells. In order to minimize the threat of chemotherapy-resistance, poison should be given sparingly. The smallest dose necessary for reducing tumor size, and not more.

Tumor is a sophisticated organ with a purpose whose nature medicine still fails to understand.

Bibliography

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